title: Relevance of uric acid and asymmetric dimethylarginine for modeling cardiovascular risk prediction in chronic kidney disease patients.
abstract: BACKGROUND
  Both elevated serum uric acid and serum asymmetric dimethylarginine (ADMA) are risk factors for cardiovascular disease. We hypothesized that combined elevation of uric acid and ADMA amplifies the risk of all-cause mortality and/or cardiovascular events (CVE) in patients with chronic kidney disease (CKD).
  
  
  METHODS
  A total of 259 patients with CKD stages 1-5 were followed up in a time-to-event analysis for all-cause mortality and fatal and non-fatal CVE (including death, stroke, and myocardial infarction). Baseline measurements included serum uric acid and ADMA and endothelial function [ultrasound determined flow-mediated dilatation (FMD)].
  
  
  RESULTS
  As a measure of endothelial function, log FMD value was positively associated with log eGFR, but negatively associated with log ADMA and log uric acid levels. During follow-up (median 38 months), 24 (9.3 %) deaths, 90 (34.7 %) CVE, and 95 (36.7 %) deaths and CVE (composite outcome) occurred. In the univariate Cox analysis, patients with both serum uric acid and ADMA levels above the median had an increased risk of all-cause mortality, CVE, and the composite outcome (HR 5.06, 95 % CI 2.01-12.76; HR 4.75, 95 % CI 2.98-7.59; and HR 4.13, 95 % CI 2.66-6.43, respectively). However, after adjustment for renal-specific risk factors (glomerular filtration rate, proteinuria, and hsCRP), this association was maintained only for CVE and the composite outcome. The addition of both biomarkers into a model with traditional and renal-specific risk factors did not increase the prediction abilities of the model for none of the three outcomes.
  
  
  CONCLUSIONS
  Elevated serum uric acid and ADMA levels are associated with an increased cardiovascular risk, but their combination does not improve risk prediction. The effects are not additive, possibly because uric acid may lie in the causal pathway by which ADMA acts.
authors.affiliation: Division of Nephrology, Department of Medicine, Koc University School of Medicine, Sariyer, Istanbul, Turkey. drkanbay@yahoo.com.
authors.forename: Mehmet
authors.identifier: http://orcid.org/0000-0002-1297-0675
authors.initials: M
authors.lastname: Kanbay
authors.affiliation: Division of Nephrology, Department of Medicine, Konya Numune State Hospital, Konya, Turkey.
authors.forename: Baris
authors.initials: B
authors.lastname: Afsar
authors.affiliation: Nephrology Clinic, Dialysis and Renal Transplant Center, 'C.I. PARHON' University Hospital, Iasi, Romania.|'Grigore T. Popa' University of Medicine, Iasi, Romania.
authors.forename: Dimitrie
authors.initials: D
authors.lastname: Siriopol
authors.affiliation: Department of Nephrology, Gulhane School of Medicine, Ankara, Turkey.
authors.forename: Hilmi Umut
authors.initials: HU
authors.lastname: Unal
authors.affiliation: Department of Nephrology, Gulhane School of Medicine, Ankara, Turkey.
authors.forename: Murat
authors.initials: M
authors.lastname: Karaman
authors.affiliation: Department of Radiology, Gulhane School of Medicine, Ankara, Turkey.
authors.forename: Mutlu
authors.initials: M
authors.lastname: Saglam
authors.affiliation: Department of Nephrology, Gulhane School of Medicine, Ankara, Turkey.
authors.forename: Tayfun
authors.initials: T
authors.lastname: Eyileten
authors.affiliation: Department of Nephrology, Gulhane School of Medicine, Ankara, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Gezer
authors.affiliation: Department of Radiology, Gulhane School of Medicine, Ankara, Turkey.
authors.forename: Samet
authors.initials: S
authors.lastname: Verim
authors.affiliation: Department of Nephrology, Gulhane School of Medicine, Ankara, Turkey.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Oguz
authors.affiliation: Department of Nephrology, Gulhane School of Medicine, Ankara, Turkey.
authors.forename: Abdulgaffar
authors.initials: A
authors.lastname: Vural
authors.affiliation: IISFundacion Jimenez Diaz, School of Medicine, UAM, REDINREN, FRIAT, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado, Denver, CO, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
authors.affiliation: Nephrology Clinic, Dialysis and Renal Transplant Center, 'C.I. PARHON' University Hospital, Iasi, Romania.|'Grigore T. Popa' University of Medicine, Iasi, Romania.
authors.forename: Adrian
authors.initials: A
authors.lastname: Covic
authors.affiliation: Department of Nephrology, Gulhane School of Medicine, Ankara, Turkey.
authors.forename: Mahmut Ilker
authors.initials: MI
authors.lastname: Yilmaz
mesh_terms: D000046:Academic Medical Centers; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000209:etiology / Q000401:mortality*; D002423:Cause of Death; D015331:Cohort Studies; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000150:complications / Q000628:therapy; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D016019:Survival Analysis; D014527:Uric Acid / Q000097:blood*
chemical_list: D015415:Biomarkers; D014527:Uric Acid; C018524:N,N-dimethylarginine; D001120:Arginine
keywords: Asymmetric dimethylarginine; Cardiovascular disease; Chronic kidney disease; Uric acid