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      Determination of Asymmetric and Symmetric Dimethylarginine in Serum from Patients with Chronic Kidney Disease: UPLC-MS/MS versus ELISA

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          Abstract

          Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis, and its structural isomer symmetric dimethylarginine (SDMA) are uremic toxins accumulating in chronic kidney disease (CKD) patients. The objective of this study was to develop and validate a robust UPLC-MS/MS method for the simultaneous determination of ADMA and SDMA in human serum. Chromatographic separation after butyl ester derivatization was achieved on an Acquity UPLC BEH C18 column, followed by tandem mass spectrometric detection. After validation, the applicability of the method was evaluated by the analysis of serum samples from 10 healthy controls and 77 CKD patients on hemodialysis (CKD5HD). Both ADMA (0.84 ± 0.19 µM vs. 0.52 ± 0.07 µM) and SDMA concentrations (2.06 ± 0.82 µM vs. 0.59 ± 0.13 µM) were significantly ( p < 0.001) elevated in CKD5HD patients compared to healthy controls. In general, low degrees of protein binding were found for both ADMA and SDMA. In addition, an established commercially available ELISA kit was utilized on the same samples ( n = 87) to compare values obtained both with ELISA and UPLC-MS/MS. Regression analysis between these two methods was significant ( p < 0.0001) but moderate for both ADMA ( R = 0.78) and SDMA ( R = 0.72).

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          Most cited references63

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          Clinical epidemiology of cardiovascular disease in chronic renal disease.

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            Chronic kidney disease as cause of cardiovascular morbidity and mortality.

            To make an evidence-based evaluation of the relationship between kidney failure and cardiovascular risk, we reviewed the literature obtained from a PubMed search using pre-defined keywords related to both conditions and covering 18 years (1986 until end 2003). Eighty-five publications, covering 552 258 subjects, are summarized. All but three studies support a link between kidney dysfunction and cardiovascular risk. More importantly, the association is observed very early during the evolution of renal failure: an accelerated cardiovascular risk appears at varying glomerular filtration rate (GFR) cut-off values, which were >/=60 ml/min in at least 20 studies. Many studies lacked a clear definition of cardiovascular disease and/or used a single determination of serum creatinine or GFR as an index of kidney function, which is not necessarily corresponding to well-defined chronic kidney disease. In six studies, however, chronic kidney dysfunction and cardiovascular disease were well defined and the results of these confirm the impact of kidney dysfunction. It is concluded that there is an undeniable link between kidney dysfunction and cardiovascular risk and that the presence of even subtle kidney dysfunction should be considered as one of the conditions necessitating intensive prevention of this cardiovascular risk.
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              Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.

              Nitric oxide (NO), synthesised from L-arginine, contributes to the regulation of blood pressure and to host defence. We describe in-vitro and in-vivo evidence that NO synthesis can be inhibited by an endogenous compound, NG,NG-dimethylarginine (asymmetrical dimethylarginine, ADMA). In man, this inhibitor is found in plasma and more than 10 mg is excreted in urine over 24 h. However, in patients with end-stage chronic renal failure, who have little or no urine output, elimination is blocked and circulating concentrations of the inhibitor rise sufficiently to inhibit NO synthesis. Accumulation of endogenous ADMA, leading to impaired NO synthesis, might contribute to the hypertension and immune dysfunction associated with chronic renal failure.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Toxins (Basel)
                Toxins (Basel)
                toxins
                Toxins
                MDPI
                2072-6651
                13 May 2016
                May 2016
                : 8
                : 5
                : 149
                Affiliations
                [1 ]Department of Organic Chemistry, Separation Science Group, Ghent University, Krijgslaan 281, S4-bis, B-9000 Ghent, Belgium; jente.boelaert@ 123456gmail.com
                [2 ]Department of Internal Medicine, Nephrology Section, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium; eva.schepers@ 123456ugent.be (E.S.); griet.glorieux@ 123456ugent.be (G.G.); sunny.eloot@ 123456ugent.be (S.E.); raymond.vanholder@ 123456ugent.be (R.V.)
                Author notes
                [* ]Correspondence: frederic.lynen@ 123456ugent.be ; Tel.: +32-9-264-96-06; Fax: +32-9-264-49-98
                Article
                toxins-08-00149
                10.3390/toxins8050149
                4885064
                27187471
                962c1aab-bd01-4cf5-bf73-9d407e1b9eec
                © 2016 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 January 2016
                : 04 May 2016
                Categories
                Article

                Molecular medicine
                asymmetric dimethylarginine,symmetric dimethylarginine,uplc-ms/ms,elisa,chronic kidney disease

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