[Hyperhomocysteinemia, oxidative stress and microinflammation in chronic renal failure: their roles in atherogene]

Abstract

Objective: To investigate the relationship between hyperhomocysteinemia, oxidative stress and microinflammation in patients with chronic renal failure (CRF), and its role in the pathogenesis of atherosclerosis seen in these patients.

Methods: One hundred and fourteen CRF patients and 37 healthy volunteers were involved in the study. The levels of plasma total homocysteine (tHcy) were determined by fluorescence polarization immunoassay. Plasma malondialdehyde (MDA) levels were analyzed by thiobarbituric acid reaction. The activity of glutathione peroxidase (GSHPx) in plasma was measured by spectrophotometry. Serum C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)alpha were determined by ELISA. Intima-medial thickness (IMT) of extracranial common carotid artery and the presence of atherosclerotic plaques was determined by using noninvasive high-resolution B-mode ultrasonography.

Results: Levels of tHcy, MDA, CRP and TNFalpha in the non-dialysis CRF patients were significantly higher than those in the healthy controls and increased with the progression of renal insufficiency, while plasma activity of GSHPx decreased progressively with decline of renal function. Compared with the pre-dialysis patients, hemodialysis patients exhibited higher levels of tHcy, MDA, CRP, IL-6 and TNFalpha, and lower levels of GSHPx activity. There were no significant difference in the levels of tHcy, MDA, CRP, IL-6, TNFalpha, and GSHPx activity between patients dialyzed with hemophan, polysulfone and cellulose triacetate membrane. Prevalence of atherosclerotic plaque and increased IMT in carotid artery were significantly higher in CRF patients compared with the age-matched controls and associated with the levels of tHcy, MDA and CRP. Multivariate stepwise regressive analysis showed that increased IMT in CRF patients was closely related to the levels of tHcy, MDA, CRP, blood glucose, and very low density lipoproteins (R(2) = 0.572, P < 0.001). The factors associated with plasma MDA (representing lipid peroxidation level) were GSHPx activity (standard regressive coefficient, beta = -0.651, P < 0.01), tHcy level (beta = 0.229, P < 0.01), and serum creatinine (beta = 0.163, P < 0.05). The factors associated with serum CRP (representing microinflammation state) were IL-6 (beta = 0.532, P < 0.01), TNFalpha (beta = 0.212, P < 0.01), MDA (beta = 0.209, P < 0.05), and plasma albumin (beta = -0.297, P < 0.05).

Conclusion: Hyperhomocysteinemia in CRF patients may accelerate oxidative stress, and lipid peroxidation may be involved in the occurrence of microinflammation state. The complex interaction between hyperhomocysteinemia, oxidative stress and microinflammation may result in accelerated atherosclerosis seen in CRF.