Inflammation and advanced glycation end products in uremia: Simple coexistence, potentiation or causal relationship?

The causes for the high frequency of cardiovascular disease in dialysis pat ients are multifactorial in origin. Disturbances in the carbohydrate and li pid metabolism, the balance between oxidants and antioxidants and the immun e-inflammatory system are thought to play a role. Chronic uremia is charact erized by the accumulation of advanced glycation end products (AGEs) and ad vanced oxidation products (AOPP) as well as activation of the acute phase r esponse. High serum levels of these products and acute phase reactants such as C-reactive protein (CRP), fibrinogen and serum amyloid A can be found. CRP has been shown to predict cardiovascular and overall mortality in hemod ialysis patients. Whether CRP is involved causally in atherosclerosis or me rely represents a marker of disease is as yet unknown. Since CRP has been d etected in colocalization with modified apolipoproteins or complement compo nents in atherosclerotic lesions, a pathophysiological role seems very like ly. AGEs as well have been detected in aortas of hemodialysis patients. Inc ubation of endothelial cells with AGEs induced expression of adhesion molec ules with consecutive attraction of monocytes to the vessel wall. Thus far, clinical studies investigating the predictive effects of AGEs on cardiovas cular mortality in hemodialysis patients are lacking. There is considerable debate about what factors turn on the acute phase response in this populat ion. Proinflammatory effects of AGEs mediated through one receptor for AGEs , RAGE, have been described. We hypothesize that there may be a link betwee n increased hepatic CRP production and the accumulation of AGEs in uremia. AGEs map stimulate CRP production in hepatocytes either directly or indirec tly via interaction with monocytes.