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      Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease - a One-Year Follow-Up Study

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          Background/Aims: Asymmetric dimethylarginine (ADMA) is a prognostic factor in patients with chronic kidney disease (CKD). However, the relationships among factors influencing the metabolism of ADMA and the CKD progression are not fully understood. Methods: Serum ADMA, and variables related to the metabolism of ADMA were measured in 181 non-dialysis patients (CKD stages 3-5) and in 46 controls. Patients were assessed at baseline, and 6 and 12 months after the initiation of the study. Results: Patients had increased baseline ADMA, advanced glycation end products (AGE), and advanced oxidation protein products (AOPP) compared with controls (P<0.001). In a total of 164 patients who completed a one-year study, the estimated GFR (eGFR) declined from 23.5 (17.7-36) mL/min/1.73m<sup>2</sup> to 21 (14.7-31.5) (P=0.018), AGE rose from 1.58 (1.38-1.90) μmol/L to 1.76 (1.52-2.21) (P<0.001), while ADMA, AOPP, tubular function, and proteinuria remained stable. In a multiple regression model (adjusted R<sup>2</sup> = 0.49, P<0.0001), the interaction of relatively higher baseline eGFR, i.e. > 25 mL/min/1.73m<sup>2</sup>, with higher ADMA (P=0.02) and higher AOPP (P=0.04) predicted the severest decrease in eGFR per year. Other predictors of progression were higher baseline AGE (P<0.001), proteinuria (P=0.003), hypertension (P=0.01), and higher baseline eGFR (P=0.03). Conclusion: Elevated ADMA and markers of oxidative stress were strong predictors of progression in patients with eGFR between 25-40 mL/min/1.73m<sup>2</sup> , i.e. at the borderline of CKD stages 3-4.

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          The Role of Asymmetric Dimethylarginine (ADMA) in Endothelial Dysfunction and Cardiovascular Disease

          Endothelium plays a crucial role in the maintenance of vascular tone and structure. Endothelial dysfunction is known to precede overt coronary artery disease. A number of cardiovascular risk factors, as well as metabolic diseases and systemic or local inflammation cause endothelial dysfunction. Nitric oxide (NO) is one of the major endothelium derived vaso-active substances whose role is of prime importance in maintaining endothelial homeostasis. Low levels of NO are associated with impaired endothelial function. Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in human circulation. Elevated levels of ADMA inhibit NO synthesis and therefore impair endothelial function and thus promote atherosclerosis. ADMA levels are increased in people with hypercholesterolemia, atherosclerosis, hypertension, chronic heart failure, diabetes mellitus and chronic renal failure. A number of studies have reported ADMA as a novel risk marker of cardiovascular disease. Increased levels of ADMA have been shown to be the strongest risk predictor, beyond traditional risk factors, of cardiovascular events and all-cause and cardiovascular mortality in people with coronary artery disease. Interventions such as treatment with L-arginine have been shown to improve endothelium-mediated vasodilatation in people with high ADMA levels. However the clinical utility of modifying circulating ADMA levels remains uncertain.
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            Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study

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              The determinants of endothelial dysfunction in CKD: oxidative stress and asymmetric dimethylarginine.

              Oxidative stress is related to endothelial dysfunction (ED) and cardiovascular outcomes in patients with chronic kidney disease. Increased asymmetric dimethylarginine (ADMA) levels are among the main causes of ED. We aim to investigate any association between ED and ADMA levels, as well as levels of oxidative stress markers, in patients with chronic kidney disease. One hundred fifty-nine patients without diabetes with chronic kidney disease were studied. Staging was performed according to glomerular filtration rate, determined as stages 1 to 5 according to the Kidney Disease Outcomes Quality Initiative (n = 30, 33, 28, 32, and 36, respectively). The control group consisted of 30 healthy subjects. Oxidative stress markers (plasma malondialdehyde [MDA], erythrocyte superoxide dismutase [SOD], glutathione peroxidase [GSH-Px]), trace elements (erythrocyte zinc [EZn], erythrocyte copper [ECu]), plasma selenium (Se), and serum ADMA were studied. Brachial artery endothelium-dependent vasodilatation (FMD) was calculated for all. FMD, SOD, GSH-Px, EZn, ECu, and Se values were lower, whereas MDA and ADMA levels were higher in patients than controls. Glomerular filtration rate correlated negatively with MDA and ADMA levels and positively with FMD, SOD, and GSH-Px values. These parameters were significantly different among patients with stages 2, 3, 4, and 5 (hemodialysis group; P < 0.001 for all). Regression analysis showed that ADMA (beta = -0.228; P < 0.01), SOD (beta = 0.405; P < 0.001), and oxidized low-density lipoprotein levels (beta = -0.428; P < 0.001) were related independently to FMD, whereas glomerular filtration rate was not involved in the model. The present results imply that FMD, oxidative stress, and ADMA levels all are associated with stage of chronic kidney disease. Additionally, levels of oxidative stress markers and ADMA independently determine endothelial function.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                July 2014
                03 June 2014
                : 39
                : 1
                : 50-57
                aDepartment of Internal Medicine I; bInstitute of Clinical Biochemistry and Hematology, Charles University, Medical School and Teaching Hospital Plzeň, Czech Republic
                Author notes
                *Jaromír Eiselt, MD, PhD, Department of Internal Medicine I, Alej Svobody 80, 323 00 Plzeň (Czech Republic), Tel. +420 377 103 925, Fax +420 377 103 970, E-Mail
                355776 Kidney Blood Press Res 2014;39:50-57
                © 2014 S. Karger AG, Basel

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                Pages: 8
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