Sympathetic nerve traffic and asymmetric dimethylarginine in chronic kidney disease

Summary

Background and objectives

Sympathetic overactivity and high levels of the endogenous inhibitor of NO synthase asymmetric dimethylarginine (ADMA) are prevalent risk factors in chronic kidney disease (CKD).

Design, setting, participants, & measurements

In 48 stage 2 to 4 CKD patients, we investigated the relationship between efferent postganglionic muscle sympathetic nerve traffic (microneurography) and circulating ADMA and analyzed the links between these risk factors and estimated GFR (eGFR), proteinuria, and different parameters of left ventricular (LV) geometry.

Results

CKD patients characterized by sympathetic nerve traffic values in the third tertile showed the highest ADMA levels, and this association was paralleled by a continuous, positive relationship between these two risk factors (r = 0.32, P = 0.03) independent of other confounders. Both sympathetic nerve traffic and ADMA were inversely related to eGFR and directly to proteinuria and LV geometry. Remarkably, the variance of eGFR, proteinuria, and LV geometry explained by sympathetic nerve traffic and ADMA largely overlapped because sympathetic nerve traffic but not ADMA was retained as a significant correlate of the eGFR (P < 0.001) and of the relative wall thickness or the left ventricular mass index/LV volume ratio (P = 0.05) in models including both risk factors. ADMA, but not sympathetic nerve traffic, emerged as an independent correlate of proteinuria (P = 0.003) in a model including the same covariates.

Conclusions

Sympathetic activity and ADMA may share a pathway leading to renal disease progression, proteinuria, and LV concentric remodeling in CKD patients.     

血清非对称性二甲基精氨酸与冠心病严重程度的相关性

目的 探讨血清非对称性二甲基精氨酸（ADMA）水平与冠心病严重程度的相关性。方法 冠脉造影确诊的冠心病患者45例,依据冠心病临床类型分为急性心肌梗死组（n=22例）和心绞痛组（包括稳定型心绞痛和不稳定型心绞痛,n=23）。患者在入院后采集病史,测定心肌酶、三酰甘油（TG）、总胆固醇(TC)、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）、高敏C反应蛋白（hs-CRP）和血清ADMA。同时用Syntax积分来评估冠脉狭窄程度,比较组间ADMA水平,分析ADMA水平与TG、TC、LDL-C、HDL-C、hs-CRP以及Syntax积分的相关性。结果 急性心肌梗死组血清ADMA水平(60±24) μg/L显著高于心绞痛组(31±21) μg/L,P<0.05。患者血清ADMA水平与LDL-C、hs-CRP呈正相关。患者血清ADMA水平与冠脉狭窄程度的Syntax积分呈正相关。结论 血清ADMA水平与冠心病严重程度有相关性。     

非对称性二甲基精氨酸和胱氨酸蛋白酶抑制剂C与冠心病

目的 探讨冠状动脉疾病中血浆非对称性二甲基精氨酸(ADMA)与胱氨酸蛋白酶抑制剂C(Cystatin C)之间的关系.方法 选取冠心病患者87例(其中急性心肌梗死39例,不稳定性心绞痛48例),健康对照组51例;同时,依据Cystatin C水平将冠心病患者分为Cystatin C升高组(51例)与无Cystatin C升高组(36例),采用高效液相色谱法测定血浆中ADMA、对称性二甲基精氨酸(SDMA)、左旋精氨酸(L-Arg)的含量,采用德国BNProSpec全自动速率散色比浊仪测定血浆Cystatin C的含量.结果 冠心病患者血浆ADMA[(0.47±0.15)μmol/L比(0.37±0.15)μmol/L]、SDMA[(0.39±0.19)μmol/L比(0.28±0.12)μmol/L]和Cystatin C浓度[(1.16±0.32)mg/L比(0.73±0.16)mg/L]均高于正常对照组(P均<0.05),L-Arg浓度低于正常对照组[(59.4±19.4)μmol/L比(83.7±19.6)μmol/L,P<0.05];对冠心病组的亚组分析显示血浆ADMA、L-Arg和Cystatin C浓度在心肌梗死组较心绞痛组差异无统计学意义.在Cystatin C<1 mg/L的冠心病患者中血浆ADMA与正常对照组比较,差异无统计学意义;而在Cystatin C>1 mg/L的冠心病患者血浆ADMA高于正常对照组[(0.50±0.17)μmol/L比(0.39±0.15)μmol/L,P<0.05].结论 只有在血浆Cystatin C水平升高的冠心病患者血浆ADMA水平才明显升高,提示冠心病患者血浆ADMA水平的升高并不与冠心病直接相关,可能与冠心病患者伴随轻微肾损害有关.     

Circulating levels of asymmetric dimethylarginine are an independent risk factor for left ventricular hypertrophy and predict cardiovascular events in pre-dialysis patients with chronic kidney disease

BackgroundSeveral studies have related the circulating level of asymmetric dimethylarginine (ADMA) to cardiac remodeling and cardiovascular (CV) events in end-stage renal disease (ESRD) patients. Studies investigating this relationship in patients with pre-dialysis chronic kidney disease (CKD) are lacking.MethodsWe enrolled 76 CKD patients (age, 46.7 ± 14.3 years, 39 females) and 15 controls (age, 40.1 ± 18.5 years, 6 females). Clinical parameters, blood biochemistry and echocardiographic findings were recorded, and plasma ADMA concentrations measured by high-performance liquid chromatography–mass spectrometry (HPLC–MS). Patients were prospectively followed up for a median of 15 (range, 6–24) months.ResultsPlasma ADMA was significantly elevated in CKD patients compared with controls (41.56 ± 12.76 μg/mL vs 17.12 ± 7.09 μg/mL, P < 0.001), and correlated with the left ventricular mass index (LVMI) (r = 0.597, P < 0.001). During follow-up, 25 patients experienced new CV events and their plasma ADMA level was significantly elevated (48.27 ± 13.70 vs 34.91 ± 6.38 in CV event-free patients, P < 0.001). Cox regression analysis further confirmed that ADMA was an independent risk factor for CVD (HR = 1.175, 95%CI[1.070–1.290], P = 0.001).ConclusionSimilar to findings in ESRD patients, elevated circulating levels of ADMA may increase the risk of LVH and CV events in pre-dialysis CKD patients.     

Putative role of asymmetric dimethylarginine in microvascular disease of kidney and heart in hypertensive patients

BACKGROUND: Despite the frequent simultaneous presentation of cardiac and renal dysfunction, the relationship between these pathophysiological processes remains unclear. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase, which has been linked to endothelial dysfunction and atherosclerosis. This study elucidates the relationship between ADMA and intrarenal and coronary microvascular diseases. METHODS: In this study, we included 66 consecutive hypertensive patients with normal renal function or mild renal insufficiency (creatinine or=90 ml/min; renal insufficiency group, eGFR <90 ml/min). Coronary flow velocity reserve (CFVR) was measured using adenosine-triphosphate stress transthoracic Doppler echocardiography. In addition, a plasma ADMA assay, echocardiography, carotid ultrasound, and brachial-ankle pulse wave velocity measurement were performed. RESULTS: The plasma ADMA level was the highest in patients with both renal insufficiency and reduced CFVR. ADMA was significantly associated with eGFR (r = -0.342, P = 0.006) and CFVR (r = -0.459, P < 0.001), and eGFR and CFVR were significantly associated with each other (r = 0.337, P = 0.006). Multiple regression analysis revealed that ADMA was an independent clinical parameter associated with both eGFR and CFVR. CONCLUSIONS: Plasma ADMA is suggested to be an incipient biochemical marker of microvascular disease in both kidney and heart in hypertensive patients. ADMA might play an important role in the pathogenesis of organ damage in the kidney and heart in essential hypertension.     

冠心病患者循环内皮祖细胞与血浆非对称二甲基精氨酸的相关分析

目的探讨冠心病患者循环内皮祖细胞(EPCs)水平与血浆非对称二甲基精氨酸(ADMA)浓度的相关性及临床意义。方法将确诊或疑似冠心病的87例患者分为2组,经冠状动脉造影证实冠心病的患者55例为冠心病组,造影证实非冠心病患者32例为非冠心病组,采用流式细胞技术分析外周血循环EPCs水平,高效液相色谱分析法检测血浆ADMA浓度。结果冠心病组患者EPCs(0.033±0.014)%较非冠心病组(0.054±0.013)%显著降低,冠心病组患者血浆ADMA(0.374±0.059)mg/L较非冠心病组(0.317±0.023)mg/L显著升高(P<0.01);冠心病组循环EPCs水平与血浆ADMA浓度呈负相关(r=-0.691,P<0.01)。结论冠心病患者高浓度的血浆ADMA可能是外周血循环EPCs水平降低的原因之一。     

Plasma levels of asymmetric dimethylarginine in patients with biopsy-proven nonalcoholic fatty liver disease

Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are produced by breakdown of proteins that have been methylated posttranslationally at an arginine residue. Plasma levels of ADMA are elevated in insulin resistance states. Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance and varying degrees of hepatic dysfunction. Because ADMA is metabolized in the liver, we hypothesized that ADMA levels will be high in patients with NAFLD as a consequence of hepatic dysfunction and insulin resistance. Plasma levels of ADMA, SDMA, total homocysteine, glucose, and insulin were measured in nondiabetic patients with biopsy-proven NAFLD (11 steatosis and 24 nonalcoholic steatohepatitis) and 25 healthy subjects. Plasma ADMA levels were significantly higher (P = .029) in patients with biopsy-proven NAFLD (0.43 ± 0.21 μmol/L) compared with controls (0.34 ± 0.10 μmol/L). However, when adjusted for insulin resistance (homeostasis model assessment), the difference between 2 groups was not evident. Plasma SDMA levels were similar in all 3 groups. Plasma levels of ADMA were positively correlated with plasma total homocysteine levels (P = .003). Plasma levels of SDMA were negatively correlated with estimated glomerular filtration rate (P = .016) and positively correlated with plasma total homocysteine levels (P = .003). The ratio of ADMA/SDMA was positively correlated with body mass index (P = .027). Elevated plasma concentrations of ADMA in biopsy-proven NAFLD were primarily related to insulin resistance. Hepatic dysfunction in NAFLD does not appear to make significant contribution to changes in plasma methylarginine levels.     

Positive association of serum levels of advanced glycation end products and high mobility group box–1 with asymmetric dimethylarginine in nondiabetic chronic kidney disease patients

There is accumulating evidence that engagement of the receptor for advanced glycation end products (RAGE) with ligands such as advanced glycation end products (AGEs) and high mobility group box–1 (HMGB-1) elicits vascular inflammation, thus contributing to the increased risk for cardiovascular disease. Furthermore, enhanced accumulation of asymmetric dimethylarginine (ADMA) plays a role in cardiovascular disease in chronic kidney disease (CKD) patients. However, the relationships among serum levels of AGEs, HMGB-1, soluble form of RAGE (sRAGE), and ADMA are largely unknown. The aim of the present study is to determine their relationships in CKD patients. Twenty nondiabetic normotensive CKD patients with dyslipidemia and 20 age- and sex-matched healthy controls were enrolled. All subjects underwent determination of blood chemistries; urinary proteinuria; and serum levels of AGEs, HMGB-1, sRAGE, and ADMA. Serum AGE, HMGB-1, sRAGE, and ADMA levels in CKD patients were significantly higher than those in control subjects. Circulating levels of AGEs in CKD patients were positively associated with sRAGE and ADMA, and HMGB-1 with ADMA, but not sRAGE. There were no significant associations among these markers and serum creatinine, estimated glomerular filtration rate, proteinuria, and lipid levels. In multiple regression analyses, AGEs and HMGB-1 were independently correlated with ADMA. The present study demonstrated that AGE and sRAGE levels were correlated with each other and that AGEs and HMGB-1 were independently associated with ADMA in nondiabetic CKD patients. Elevation of the RAGE ligands may enhance ADMA levels, suggesting the active involvement of AGE/HMGB-1–RAGE–ADMA axis in CKD patients.     

Plasma asymmetric dimethylarginine (ADMA) levels and atherosclerotic disease in ankylosing spondylitis: a cross-sectional study

Conclusive data about the prevalence of endothelial dysfunction and atherosclerotic process in ankylosing spondylitis (AS) patients with respect to the general population are lacking. Elevated plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been reported in clinical conditions associated with endothelial dysfunction and atherosclerotic disease. We performed a cross-sectional study to evaluate plasma ADMA levels and atherosclerotic disease in AS patients. Seventeen consecutive AS patients free of any cardiovascular disease and 17 healthy controls [strictly matched for sex, age (±5 years) and atherosclerotic risk factors] were recruited. Plasma ADMA levels were assessed by capillary electrophoresis. Common carotid artery intima–media thickness (CCA-IMT), flow-mediated dilatation (FMD) and arterial stiffness (aS) were registered as surrogate markers of atherosclerotic disease. Plasma ADMA levels appeared significantly (p = 0.001) higher in AS patients (0.65 ± 0.10 μmoli/L) than in the control subjects (0.54 ± 0.07 μmoli/L) while no statistically significant differences between AS and controls were demonstrated in CCA-IMT, FMD, and aS. AS patients showed increased plasma ADMA levels with respect to control subjects. On the contrary, we were not able to document a significant difference in atherosclerotic process between patients and controls.     

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随着人口老龄化,糖尿病和动脉粥样硬化的发病率正逐年增加,随之而来慢性肾脏病(CKD)的发病率亦日益增高,由此导致终末期肾病(ESRD)的迅速增加,带来严重的社会和经济负担。CKD进展过程中伴随肾功能的逐渐丧失和高发心血管疾病的危险。治疗CKD的主要目的是对患者进行肾脏、心血管保护,延缓肾脏病变的发展,减少ESRD的发生,防止心血管事件的发生。应用降压药治疗CKD的主要靶目标就是控制高血压,减少尿蛋白或微量白蛋白排泄量,改善或防止脏器纤维化。1慢性肾脏病的降压治疗1.1降压治疗的靶目标肾脏具有自身调节肾小球毛细血管压的能力,当…     

Endothelial damage,asymmetric dimethylarginine and cardiovascular risk in end-stage renal disease

To be appropriately labelled as a 'risk factor' any putative risk factor should increase the prediction power of standard statistical models based on 'traditional' (Framingham) risk factors. In end-stage renal disease (ESRD), Framingham risk factors do not fully explain the cardiovascular burden of these patients. Inflammation, hyperhomocysteinemia and anemia contribute to the high cardiovascular risk of ESRD, but knowledge is still incomplete. We suspected that asymmetric dimethylarginine (ADMA) is an important cardiovascular risk factor in dialysis patients. This substance inhibits nitric oxide synthase thus triggering a series of pathophysiological events leading to atherosclerosis. To test this hypothesis, we studied the relationship between ADMA and intima media thickness (IMT) in the carotid artery. ADMA was found to be strongly and independently related to IMT. More importantly we found that patients with relatively higher plasma ADMA had shorter survival and a higher rate of incident cardiovascular complications in comparison to those with a relatively lower plasma concentration. These data represent a sound basis for intervention studies aimed at modifying the plasma ADMA concentration in ESRD patients.     

Plasma asymmetric dimethylarginine and coronary and peripheral endothelial dysfunction in hypertensive patients

BACKGROUND: The attenuation of coronary flow reserve (CFR) and endothelium-mediated vasodilation of the brachial artery (EMV-BA) have been frequently reported in hypertensive patients. The present study investigated the link between CFR and EMV-BA in hypertensive patients. We hypothesized that changes in serum asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, and concomitant insulin resistance may be underlying factors connecting the two pathologic alterations. METHODS: A total of 75 patients (30 men and 45 women, 61.5 +/- 10.1 years of age) with essential hypertension and without coronary artery disease and diabetes mellitus were included in the study. Measurements of CFR were made using adenosine-triphosphate stress transthoracic Doppler echocardiography, and forearm EMV-BA was measured by venous occlusion strain gauge plethysmography. A plasma ADMA assay and a 75-g oral glucose tolerance test were also performed. RESULTS: Average CFR and EMV-BA values were 2.54 +/- 0.63 and 86.0 +/- 54.7%, respectively. A significant correlation was found between CFR and EMV-BA (r = 0.493, P <.001). Both CFR and EMV-BA were also significantly correlated with age and plasma ADMA concentration, but were not correlated with insulin resistance, plasma insulin, or left ventricular mass. Multiple regression analysis revealed that ADMA was the only statistically independent parameter associated with CFR and EMV-BA. CONCLUSIONS: The similar deterioration in endothelial function in coronary and peripheral vascular territories may be mainly due to increased plasma ADMA concentration. Plasma ADMA appears to play a major role in endothelial dysfunction in hypertensive patients, independent of insulin resistance or left ventricular hypertrophy.     

Unchanged asymmetric dimethylarginine levels in non-diabetic, premenopausal obese women who have common risk factors for cardiovascular disease

This study was performed to test whether plasma asymmetric dimethylarginine (ADMA) concentrations are related to obesity and obesity complications including decrement in insulin sensitivity and adiponectin levels, dyslipidemia and low-grade inflammation. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) concentrations were analyzed by HPLC in 17 overweight (BMI ≥ 25 kg/m²) and 40 obese (BMI ≥ 30 kg/m²) premenopausal women. Age-matched healthy women were studied as controls. Obesity did not give rise to a significant change in circulating ADMA levels but reduced in SDMA levels. As compared with control subjects (0.441 ± 0.102 μM), ADMA values in overweight and obese subjects were found to be as 0.412 ± 0.102 and 0.436 ± 0.093, respectively. No Pearson’s association of ADMA with relevant risk variables for cardiovascular disease, including blood pressure, insulin sensitivity, inflammatory markers, lipid and adiponectin levels. However, in linear regression analysis, BMI, diastolic blood pressure, glucose, insulin, and IL-8 emerged as significant predictors of ADMA. In spite of obese women have elevated hs-CRP, triglyceride levels and decreased insulin sensitivity, adiponectin and HDL-cholesterol levels, all of which is closely linked risk factors for cardiovascular disease, circulating ADMA levels remained unchanged in obese individuals as compared with controls.     

Microvascular disease and endothelial dysfunction in chronic kidney diseases: therapeutic implication

This paper was aimed to study biomarkers of endothelial injury in chronic kidney diseases. Fifty chronic kidney disease patients were subject to the following determinations: (i) circulating endothelial cells, (ii) soluble VCAM-1, (iii) transforming growth factor beta (TGFB), and (iv) intrarenal hemodynamics. Increased number of circulating endothelial cells was significantly observed. A significant depletion of vascular endothelial growth factor (VEGF) or a depleted VEGF/TGFB ratio was also documented. Results showed that sVCAM was not significantly different from normal control. Intrarenal hemodynamic alteration demonstrated a characteristic of hemodynamic maladjustment. Since increased number of circulating endothelial cells is a sensitive biomarker for endothelial cell injury in chronic kidney diseases, such injury is supported by the depletion of VEGF. The endothelial cell loss correlates with the glomerular endothelial dysfunction characterized by hemodynamic maladjustment at the efferent arteriole and reduction in peritubular capillary flow. In conclusion, correction of such hemodynamic maladjustment with multidrug vasodilators can effectively restore renal function in chronic kidney diseases.