title: Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  In vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-α was studied followed by an evaluation of nuclear factor (NF)-κB 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-α expression and a rise in active NF-κB. 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-α, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-α 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-κB and resulting in enhanced expression of IL-6 and TNF-α, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages.
authors.affiliation: Department of Internal Medicine, Nephrology Division, University Hospital Gent, De Pintelaan 185, B-9000 Gent, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Schepers
authors.forename: Daniela V
authors.initials: DV
authors.lastname: Barreto
authors.forename: Sophie
authors.initials: S
authors.lastname: Liabeuf
authors.forename: Griet
authors.initials: G
authors.lastname: Glorieux
authors.forename: Sunny
authors.initials: S
authors.lastname: Eloot
authors.forename: Fellype C
authors.initials: FC
authors.lastname: Barreto
authors.forename: Ziad
authors.initials: Z
authors.lastname: Massy
authors.forename: Raymond
authors.initials: R
authors.lastname: Vanholder
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D001530:Belgium; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D002908:Chronic Disease; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D007674:Kidney Diseases / Q000175:diagnosis / Q000276:immunology* / Q000503:physiopathology; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D011237:Predictive Value of Tests; D012372:ROC Curve; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015415:Biomarkers; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine; D000111:Acetylcysteine