Inflammation, not hyperhomocysteinemia, is related to oxidative stress andhemostatic and endothelial dysfunction in uremia

Background. Several cardiovascular risk factors are present in patients wit h chronic renal failure (CRF), among which are systemic inflammation and hy perhomocysteinemia. Increased oxidative stress, endothelial activation/dysf unction, and coagulation activation are considered integral components of t he inflammatory response, but have also been proposed as mediators of plasm a homocysteine (tHcy)-induced cell damage. Using correlation analysis, we a ssessed 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 ma rkers of these processes were studied in 64 patients with CRF (serum creati nine 526 +/- 319 mu mol/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 an d al-antitrypsin). tHcy was increased in 87.5% of patients (mean=27.1 mu mo l/L, range 6.5 to 118). Patients had significant increases in (1) indices o f oxidative stress: TBARS (thiobarbituric acid-reactive species), a marker of lipid peroxidation and AOPP (advanced oxidation protein products), a mar ker of protein oxidation; (2) endothelial cell markers such as von Willebra nd factor (vWF:Ag), soluble ICAM-1 and soluble thrombomodulin (sTM); (3) ma rkers of intravascular thrombin generation: thrombin-antithrombin complexes (TAT) and prothrombin fragment F1+2 (PF1+2); and (4) indices of activation of fibrinolysis: plasmin-antiplasmin complexes (PAP), fibrin degradation p roducts (FnDP) and fibrinogen degradation products (FgDP). tHcy was signifi cantly correlated with plasma creatinine (r=0.29, P<0.018) and with serum f olate (r=-0.38, P<0.002). However, no significant correlations were observe d between tHcy and TBARS, AOPP, vWF:Ag, sICAM-1, sTM, TAT, F1+2, sTF, PAP, FnDP, and FgDP. Conversely, acute-phase proteins showed significant, positi ve correlations with most markers of oxidative stress, endothelial dysfunct ion and hemostatic activation. Conclusions. Systemic inflammation, which is closely associated with augmen ted oxidative stress, endothelial cell dysfunction and hemostatic activatio n, emerges as a major cardiovascular risk factor in CRF. tHcy is unrelated to these events. Thus, alternative mechanisms through which hyperhomocystei nemia could predispose to vascular lesion and thrombotic events in CRF need s to be investigated.