title: Inflammation, not hyperhomocysteinemia, is related to oxidative stress and hemostatic and endothelial dysfunction in uremia.
abstract: BACKGROUND
  Several cardiovascular risk factors are present in patients with chronic renal failure (CRF), among which are systemic inflammation and hyperhomocysteinemia. Increased oxidative stress, endothelial activation/dysfunction, and coagulation activation are considered integral components of the inflammatory response, but have also been proposed as mediators of plasma homocysteine (tHcy)-induced cell damage. Using correlation analysis, we assessed the relative contributions of inflammation and hyperhomocysteinemia in the abnormal oxidative stress, endothelial activation/dysfunction, and hemostasis activation in patients with CRF.
  
  
  METHODS
  The relationships of inflammatory proteins and tHcy with plasma markers of these processes were studied in 64 patients with CRF (serum creatinine 526 +/- 319 micromol/L) on conservative treatment, comparing the results with healthy controls (N = 15 to 40, depending on the measured variable) of similar sex and age.
  
  
  RESULTS
  Patients had significant increases in inflammatory cytokines (TNF-alpha and IL-8) and acute-phase proteins (C-reactive protein, fibrinogen and alpha1-antitrypsin). tHcy was increased in 87.5% of patients (mean = 27.1 micromol/L, range 6.5 to 118). Patients had significant increases in (1) indices of oxidative stress: TBARS (thiobarbituric acid-reactive species), a marker of lipid peroxidation and AOPP (advanced oxidation protein products), a marker of protein oxidation; (2) endothelial cell markers such as von Willebrand factor (vWF:Ag), soluble ICAM-1 and soluble thrombomodulin (sTM); (3) markers of intravascular thrombin generation: thrombin-antithrombin complexes (TAT) and prothrombin fragment F(1+2) (PF(1+2)); and (4) indices of activation of fibrinolysis: plasmin-antiplasmin complexes (PAP), fibrin degradation products (FnDP) and fibrinogen degradation products (FgDP). tHcy was significantly correlated with plasma creatinine (r = 0.29, P < 0.018) and with serum folate (r = -0.38, P < 0.002). However, no significant correlations were observed between tHcy and TBARS, AOPP, vWF:Ag, sICAM-1, sTM, TAT, F(1+2), sTF, PAP, FnDP, and FgDP. Conversely, acute-phase proteins showed significant, positive correlations with most markers of oxidative stress, endothelial dysfunction and hemostatic activation.
  
  
  CONCLUSIONS
  Systemic inflammation, which is closely associated with augmented oxidative stress, endothelial cell dysfunction and hemostatic activation, emerges as a major cardiovascular risk factor in CRF. tHcy is unrelated to these events. Thus, alternative mechanisms through which hyperhomocysteinemia could predispose to vascular lesion and thrombotic events in CRF needs to be investigated.
authors.affiliation: Departments of Hematology-Oncology and Nephrology, School of Medicine, Catholic University of Chile, P.O. Box 114-D, Santiago, Chile. dmezzano@med.puc.cl
authors.forename: D
authors.initials: D
authors.lastname: Mezzano
authors.forename: E O
authors.initials: EO
authors.lastname: Pais
authors.forename: E
authors.initials: E
authors.lastname: Aranda
authors.forename: O
authors.initials: O
authors.lastname: Panes
authors.forename: P
authors.initials: P
authors.lastname: Downey
authors.forename: M
authors.initials: M
authors.lastname: Ortiz
authors.forename: R
authors.initials: R
authors.lastname: Tagle
authors.forename: F
authors.initials: F
authors.lastname: González
authors.forename: T
authors.initials: T
authors.lastname: Quiroga
authors.forename: M S
authors.initials: MS
authors.lastname: Caceres
authors.forename: F
authors.initials: F
authors.lastname: Leighton
authors.forename: J
authors.initials: J
authors.lastname: Pereira
mesh_terms: D000328:Adult; D000368:Aged; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D006487:Hemostasis; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D007249:Inflammation / Q000150:complications*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D012307:Risk Factors; D013927:Thrombosis / Q000209:etiology; D014511:Uremia / Q000150:complications*
chemical_list: D006710:Homocysteine