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Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease

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Abstract
Background & objectives Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA). Design, setting, participants, & measurements In vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-alpha was studied followed by an evaluation of nuclear factor (NF)-kappa B activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo. Results Monocytes incubated with SDMA showed increased IL-6 and TNF-a expression and a rise in active NF-kappa B. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 +/- 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-alpha, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-alpha at a high significance for SDMA (P < 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 +/- 0.05) directly followed that of C-reactive protein (AUC: 0.82 +/- 0.04) and albumin (AUC: 0.72 +/- 0.05; for all, P < 0.0001) and preceded that of ADMA (P = 0.002). Conclusions The present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-kappa B and resulting in enhanced expression of IL-6 and TNF-alpha, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages.
Keywords
CARDIOVASCULAR MORTALITY, IN-VITRO, LUDWIGSHAFEN RISK, DIALYSIS PATIENTS, N-ACETYLCYSTEINE, PROMYELOCYTIC LEUKEMIA-CELLS, STAGE RENAL-DISEASE, KAPPA-B, ASYMMETRIC DIMETHYLARGININE, CORONARY-ARTERY-DISEASE

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Chicago
Schepers, Eva, Daniela V Barreto, Sophie Liabeuf, Griet Glorieux, Sunny Eloot, Fellype C Barreto, Ziad Massy, and Raymond Vanholder. 2011. “Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease.” Clinical Journal of the American Society of Nephrology 6 (10): 2374–2383.
APA
Schepers, E., Barreto, D. V., Liabeuf, S., Glorieux, G., Eloot, S., Barreto, F. C., Massy, Z., et al. (2011). Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease. CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 6(10), 2374–2383.
Vancouver
1.
Schepers E, Barreto DV, Liabeuf S, Glorieux G, Eloot S, Barreto FC, et al. Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease. CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY. 2011;6(10):2374–83.
MLA
Schepers, Eva, Daniela V Barreto, Sophie Liabeuf, et al. “Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease.” CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 6.10 (2011): 2374–2383. Print.
@article{1997530,
  abstract     = {Background \& objectives Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA). 
Design, setting, participants, \& measurements In vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-alpha was studied followed by an evaluation of nuclear factor (NF)-kappa B activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo. 
Results Monocytes incubated with SDMA showed increased IL-6 and TNF-a expression and a rise in active NF-kappa B. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 +/- 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-alpha, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-alpha at a high significance for SDMA (P {\textlangle} 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 +/- 0.05) directly followed that of C-reactive protein (AUC: 0.82 +/- 0.04) and albumin (AUC: 0.72 +/- 0.05; for all, P {\textlangle} 0.0001) and preceded that of ADMA (P = 0.002). 
Conclusions The present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-kappa B and resulting in enhanced expression of IL-6 and TNF-alpha, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages.},
  author       = {Schepers, Eva and Barreto, Daniela V and Liabeuf, Sophie and Glorieux, Griet and Eloot, Sunny and Barreto, Fellype C and Massy, Ziad and Vanholder, Raymond},
  issn         = {1555-9041},
  journal      = {CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY},
  keyword      = {CARDIOVASCULAR MORTALITY,IN-VITRO,LUDWIGSHAFEN RISK,DIALYSIS PATIENTS,N-ACETYLCYSTEINE,PROMYELOCYTIC LEUKEMIA-CELLS,STAGE RENAL-DISEASE,KAPPA-B,ASYMMETRIC DIMETHYLARGININE,CORONARY-ARTERY-DISEASE},
  language     = {eng},
  number       = {10},
  pages        = {2374--2383},
  title        = {Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease},
  url          = {http://dx.doi.org/10.2215/CJN.01720211},
  volume       = {6},
  year         = {2011},
}

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