title: Methylarginines and mortality in patients with end stage renal disease: a prospective cohort study.
abstract: OBJECTIVE
  Methylarginines like asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are formed by post-translation methylation of arginine residues in proteins. ADMA inhibits nitric-oxide synthase and predicts clinical outcomes in various diseases including end stage renal disease (ESRD). SDMA competes with L-arginine for cell entry and is associated with organ failure in patients with severe illness. We investigated the inter-relationships between methylargines, L-arginine and other risk factors and tested the prediction power of methylargines for mortality in a prospective cohort study including 288 ESRD patients.
  
  
  RESULTS
  ADMA and SDMA exceeded the upper limit of the corresponding normal range in almost all cases (98% and 100%, respectively) and were inter-related (r=0.30, P<0.001) but only ADMA was associated with L-arginine. SDMA, was inversely related with haemoglobin (r=-0.23, P<0.001) and this association was independent of other risk factors. During the follow-up, 140 patients died. In unadjusted analysis, ADMA was strongly related to death [hazard ratio (HR) (1micromol/L): 2.07, 95% CI: 1.31-3.26] while plasma SDMA and L-arginine were largely unrelated to survival. In a multiple Cox regression model adjusting for potential confounders, ADMA maintained an independent relationship with death [HR: 1.92, 95% CI: 1.16-3.16].
  
  
  CONCLUSIONS
  Methylarginines ADMA and SDMA are inter-related. ADMA is associated with L-arginine while SDMA correlates inversely with haemoglobin. ADMA but not SDMA is a death predictor in ESRD. Given the exceedingly high risk for death of this population, establishing whether or not ADMA is causally implicated in the high death risk of ESRD is a research priority.
authors.affiliation: Dialysis Unit, Lastaria Hospital, ASL Foggia, Lucera (FG), Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Aucella
authors.forename: Renke
authors.initials: R
authors.lastname: Maas
authors.forename: Mimmo
authors.initials: M
authors.lastname: Vigilante
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tripepi
authors.forename: Edzard
authors.initials: E
authors.lastname: Schwedhelm
authors.forename: Maurizio
authors.initials: M
authors.lastname: Margaglione
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
authors.forename: Rainer
authors.initials: R
authors.lastname: Boeger
authors.forename: Carmine
authors.initials: C
authors.lastname: Zoccali
mesh_terms: D000328:Adult; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000401:mortality* / Q000628:therapy; D008297:Male; D008745:Methylation; D008875:Middle Aged; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D006435:Renal Dialysis; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D006454:Hemoglobins; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine