Attilio Losito, Renal Unit, Policlinico Monteluce, Perugia, Italy

Transcription

1 A NEW PLAYER IN CAROTID ARTERY DISEASE IN DIALYSIS PATIENTS: THE GENETIC POLYMORPHISM OF THE ENDOTOXIN RECEPTOR CD 14 Attilio Losito, Renal Unit, Policlinico Monteluce, Perugia, Italy Introduction Cardiovascular risk in patients with end-stage renal disease (ESRD) on dialytic treatment is much higher than in the general population [1]. Early research pointed to accelerated atherosclerosis as responsible for the cardiovascular morbidity and mortality in long-term maintenance hemodialysis [2]. Although the so-called conventional risk factors such as hypertension, dyslipidemia, diabetes mellitus, and smoking operate also in dialysis patients, they do not fully account for the magnitude of the atherosclerotic process in this particular population. Therefore, recently a great deal of research has been addressed to risk factors that are particularly present in ESRD or in dialytic treatment. Among others, inflammation is now regarded as one of the primary and most important mechanisms in atherogenesis [3]. In hemodialysis patients an activated acute phase response, revealed by elevated C-reactive protein, has been shown to be associated with high cardiovascular death rate [4]. Proinflammatory cytokines, such IL-6, have been frequently found to be elevated in hemodialysis patients [5]. The association of high levels of IL-6 with carotid atherosclerosis has been considered a confirmation of the role of inflammation in the atherosclerotic process in dialysis [6]. This cytokine seems to be at the center of a vicious circle that comprises inflammation, malnutrition, and cardiovascular disease [7]. Studies on genetic polymorphisms of IL-6 in hemodialysis patients also support its role in cardiovascular disease of ESRD [8]. Chronic hemodialysis should be regarded as a complex state where procedure-related and disease factors coexist. In this setting other proinflammatory substances with potential atherogenic properties may play a role. Endotoxin and scd14 The hemodialytic procedure is associated with an exchange of substances through membranes of different degrees of permeability. Years ago passage of bacterial endotoxin, from clinically used

2 dialysate to the blood, through dialytic membranes of different types, was demonstrated [9]. In the general population raised concentrations of endotoxin are found in association with heart failure suggesting that endotoxin may trigger immune activation during edematous episodes [10] Other research have shown that circulating endotoxin provokes severe endothelial dysfunction and may be an important atherogenic factor [11].Strong support to this hypothesis has been provided by a large epidemiological study on the general population. In the study, plasma endotoxin levels were measured and carotid disease was assessed simultaneously. The results showed that subjects with high levels of circulating endotoxin had a high risk of carotid atherosclerosis [12]. The atherosclerotic risk was higher in smoker and ex-smokers. CD 14 is a pattern recognition receptor, on the membranes of monocytes and macrophages, for bacteria produced endotoxin. A soluble form of CD14 (scd14) is present in serum, whose role is the control of the bioactivity of circulating endotoxin: high levels of scd14 enhance the blood clearance of endotoxin [13]. CD14, after binding with bacterial lipopolysaccharides evokes the endothelial activation and the secretion of proinflammatory cytokines, followed by a complex cascade of events that eventually leads to the atherosclerotic lesion. The final effect of this mechanism is on the vulnerability of the atherosclerotic plaque. The scd14 is therefore at the crossroads between infection and inflammation [14]. The levels of circulating scd14 are regulated by a genetic-environmental interaction. A recently discovered polymorphism (-59C/T) in the gene of CD14 has been shown to control the levels of circulating scd14 in interaction with infections and bacterial contamination [15]. A recent report has in fact described the association between this polymorphism and coronary artery disease (CAD) patients chronically infected with C. pneumoniae [16]. Subsequent research on the association of this polymorphism and cardiovascular disease has produced variable and sometimes conflicting results. In some cases an association of this polymorphism with cardiovascular disease was found, while other studies did not confirm this association [17,18]. Unfortunately most of the reported studies are of the cross-sectional type and the indices of disease examined differ substantially. Another explanation of these controversial results may lie with the genetic-environmental interaction. In fact, identifying genetic variants as a single cause of cardiovascular disease would be an oversimplification. Instead, the contribution of these polymorphisms should also be considered in the context of nongenetic risk factors (e.g. smoking, diabetes, hyperlipidemia) and the examined patients populations. In the general population an interesting relationship has been found between smoking habits, carotid atherosclerosis, and the CC genotype of this polymorphism [19]. Since endotoxemia is a mediator of inflammation, and smokers have elevated plasma levels of endotoxin, carriers of the CC genotype may be at risk of atherosclerosis because the reduced clearance of endotoxin associated with the C allele of the - 159C/T polymorphism. It has also been suggested that this polymorphism is a marker for smoking dependence with all its consequences [20]. Therefore the possible role of this polymorphism is to be searched not in the general population, but in subsets of patients exposed at a genetic-environmental interaction. Patients chronically treated with hemodialysis may be an example. Polymorphism of scd14, Hemodialysis, and Carotid Disease Carotid disease is found frequently in ESRD and has been associated with a poor outcome. Risk factors for carotid atherosclerosis have been related to complications of ESRD, mostly linked to chronic inflammation or to abnormal levels of toxic mediators [21,22]. A genetic enhancement

3 of the toxic effect of angiotensin II associated with ESRD has been also suggested [23]. The population of dialysis patients with chronic exposure to exogenous endotoxin represents a model in which to verify the genetic-environmental interaction and its effect on the atherosclerotic process. In patients with ESRD who are undergoing chronic hemodialysis, increased serum levels of scd14 have been found, possibly as a response to chronic exposure to trace amounts of endotoxin [24]. The rise of scd14 levels were observed during acute or chronic infections and are the effect of the combination between immune response and a functional genetic trait. Carriers of the CC genotype of the -159C/T polymorphism not only produce lower levels of scd14 as immune response compared to TT carriers but also present lower baseline serum levels [25]. This finding confirms the functional nature of this genetic polymorphism. The theoretical consequence is that carriers of CC genotype have slower clearance of bacterial endotoxin, and therefore are more exposed to the toxic effects of this substance. Indirect evidence that endotoxin may be a cause of carotid disease in ESRD, comes from the finding of an association between smoking and atherosclerosis in dialysis patients [26]. A putative link between smoking, endotoxemia, and atherosclerosis is the CD14 receptor, and in turn its polymorphism [19]. The association of this polymorphism with carotid atherosclerosis and cardiovascular mortality has been investigated in a cohort of ESRD patients. The multivariate analysis showed that age, smoking, and the -159C/T polymorphism were independent predictors of carotid disease [27]. Carriers of the CC genotype had a relative risk of 8.5 compared to the TT (95% CI = ). In the longitudinal part of the study the association of cardiovascular mortality with different risk factors was assessed. The Cox analysis produced a model with the following predictors: age, serum albumin, hypertension, and CD14 polymorphism. All these selected variables are known risk factors for cardiovascular disease in ESRD, the new one is the CD14 polymorphism. The results of this study confirm that performing genetic association studies in the search of a single genetic cause of cardiovascular disease may be an impossible task [28]. The analysis of genetic-environment interaction with functional polymorphisms in selected populations may instead be more meaningful. It may allow insights into the pathogenetic putative mechanism. This type of study, in selected populations, may also contribute to design specifically aimed at therapeutic interventions. References 1. Foley R, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998;32(Suppl 3):S112-S Lindner A, Charra B, Sherrad DJ, Scribner BH. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Eng J Med 1974;290: Ross R. Atherosclerosis an inflammatory disease. N Eng J Med 1999;340: Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999;55: Herbelin A, Urena P, Nguye AT, et al. elevated circulating levels of interleukin-6 in patients with chronic renal failure. Kidney Int 1991;39: Stenvinkel P, Heimbürger O, Jogestrand T. Elevated interleukin-6 predicts progressive carotid atherosclerosi in dialysis patients: Association to chlamidia pneumoniae seropositivity. Am J Kidney Dis 2002;39: Stenvinkel P, Barany P, Heimbürger O, Pecoits-Filho R, Lindholm B. Mortality, malnutrition, and atherosclerosis in ESRD: what is the role of interleukin-6? Kidney Int 2002;61(Suppl 80):s103-s108.

4 8. Losito A, Kalidas K, Santoni S, Jeffery S. Association of interleukin G/C promoter polymorphism with hypertension and left ventricular hypertrophy in dialysis patients. Kidney Int 2003;64: Lade-Sharp M, Caroff M, Simard L, Pusineri C, Kazatchkine MD, Haeffner-Cavaillon N. Induction of IL1 during hemodialysis: transmembrane passage of intact endotoxin (LPS). Kidney Int 1990;38: Niebauer J. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 1999;353: Bhagat K, Moss R, Collier J, Vallance P. Endothelial stunning following a brief exposure to endotoxin: a mechanism to link infection and infarction? Cardiovasc Res 1996;32: Wiedermann CJ, Kiechl S, Dunzendorfer S, et al. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck study. J Am Coll Cardiol 1999;34: Hiki N, Berger D, Dentener MA, et al. Changes in endotoxin-bending proteins during major elective surgery: important role for soluble CD14 in regulation of biological activity of systemic endotoxin. Clin Diagn Lab Immunol 1999;6: Arroyo-Espliguero R, Avanzas P, Jeffery S, Kaski JC. CD14 and toll-like receptor 4: a link between infection and acute coronary events? Heart 2004;90: Baldini M, Lohman IC, Halonen M, Ericson RP, Holt PG, Martinez F. A polymorphism* in the 5 flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 1999;20: Rupp J, Goepel W, Kramme E, Jahn J, Solbach W, Maass M. CD14 promoter polymorphism - 159C>T is associated with susceptibility to chronic Chlamydia pneumoniae infection in peripheral blood monocytes. Genes Immun 2004;5(5): Koch W, Kastrati A, Mehilli J, von Beckerath N, Schomig A. CD14 gene -159C/T polymorphism is not associated with coronary artery disease and myocardial infarction. Am Heart J 2002;143: Agema WR, Wouter Jukema J, de Maat MP, et al. Pharmacogenetics of the CD14 endotoxin receptor polymorphism and progression of coronary atherosclerosis. Thromb Haemost 2004;91: Risley P, Jerrard-Dunne P, Sitzer M, Buehler A, von Kegler S, Markus HS. Promoter polymorphism in the endotoxin receptor (CD14) is associated with increased carotid atherosclerosis only in smokers: the Carotid Atherosclerosis Progression Study. Stroke 2003;34: Hubacek J, Pitha J, Skodova z, Poledne R. Is the CD14 receptor gene a marker for smoking dependence? Med Sci Monit 2002;8:BR Zoccali C, Benedetto FA, Mallamaci F, et al. Inflammation is associated with carotid atherosclerosis in dialysis patients. J Hypertens 2000;18: Boger RH, Zoccali C. ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease. Atheroscler Suppl 2003;4: Losito A, Kalidas K, Santoni S, Ceccarelli L, Jeffery S. Polymorphism of the renin angiotensin system genes in dialysis patients association with cerebrovascular disease. Nephrol Dial Transplant 2002;17: Nockher WA and Scherberich JE. Monocyte cell-surface CD14 expression and soluble CD14 antigen in hemodialysis: Evidence for chronic exposure to LPS. Kidney Int 1995;48: Kabesch M, Hasemann K, Schickinger V, et al. A promoter polymorphism in the CD14 gene is associated with elevated levels of soluble CD14 but not with IgE or atopic diseases. Allergy 2004;59: Malatino LS, Benedetto FA, Mallamaci F, et al. Smoking, blood pressure and serum albumin are major determinants of carotid atherosclerosis in dialysis patients. J Nephrol 1999;12:

5 27. Losito A, Kalidas K, Santoni S, Errico R, Jeffery S. Association of the -159C/T polymorphism of the endotoxin receptor (cd14) with carotid artery disease and cardiovascular mortality in dialysis patients. Blood Purif. 2005;23(2): Kandzari DE, Goldschmidt-Clermont PJ. Making positive out of negative trials. Am Heart J 2002;143: