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).
Highlights
Chronic kidney disease (CKD) is a worldwide public health problem with cardiovascular disease as the most important and often fatal complication [1,2]
asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of nitric oxide synthase by competing with L-arginine as the substrate [5]
Detection was performed by tandem mass spectrometry operated in multiple reaction monitoring (MRM) mode, which is characterized by its sensitivity and selectivity and widely implemented in bioanalysis
Summary
Chronic kidney disease (CKD) is a worldwide public health problem with cardiovascular disease as the most important and often fatal complication [1,2]. A myriad of toxic solutes, normally cleared by the kidneys, among which asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), accumulate in the body of CKD patients [3]. Both originate from proteolysis of methylated proteins [4]. Elevated plasma ADMA levels have been associated with endothelial dysfunction [5,6], which is an essential contributing element to vascular disease, and were found in patients with various risk factors for atherosclerosis such as in CKD [7,8]. Plasma ADMA levels may predict the progression of renal injury in patients with early-stage CKD [9,10], and are an independent risk factor for cardiovascular disease
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