Department of Nephrology and Internal Intensive Care Medicine, Charité-Campus Virchow-Klinikum, Humboldt University of Berlin, Berlin, Germany
Keywords: C-reactive protein; cardiovascular risk; inflammatory mediators
Inflammatory mediators and cardiovascular risk
Over recent years an association between cardiovascular events and inflammation has been reported by several groups and this now finally appears to be well established. Baseline levels of C-reactive protein (CRP) in apparently healthy individuals represent an independent risk factor for cardiovascular events including myocardial infarction and peripheral artery disease [13]. Moreover, the rise in CRP after myocardial infarction, or during unstable angina pectoris, predicts outcome [4]. It has been suggested that the inflammatory process may not merely be an epiphenomenon but rather a pathogenetical factor in the genesis of atherosclerosis [5].
Cardiovascular mortality is greatly increased in haemodialysis patients. For instance, the risk of dying from cardiovascular causes is 100-fold higher for a 40-year-old dialysis patient compared to the normal population [6]. Besides other explanations (hypertension, hyperlipidaemia), one reason may be the chronic inflammation observed in patients with renal failure, as indicated by elevated plasma levels of acute phase proteins such as CRP [7] and elevated levels of cytokines such as interleukin-6 (IL-6) [8]. Moreover, the capacity of monocytes from patients with renal failure to produce cytokines appears to be augmented. Indeed, even in dialysis patients, plasma levels of CRP and IL-6 are strong predictors for mortality in subsequent years [9,10]. The causes for the inflammatory response in patients with renal failure are not obvious. There are several potential sources, including bacterial contamination of the dialysate, dialyser membrane incompatibility and infections of the vascular access. However, the dialysis procedure may only be partially responsible because even patients with renal insufficiency who are not yet on dialysis have elevated levels of CRP that rise further after starting regular haemodialysis treatment [11]. Thus, accumulation of mediators (pro-inflammatory cytokines, advanced glycation end products) in renal failure may contribute to inflammation. Descamps-Latscha et al. [12] demonstrated that plasma levels of IL-1 receptor antagonist were significantly increased from the earliest stage of renal failure. Plasma levels of TNF- and soluble TNF-receptors progressed with the severity of renal failure and correlated with glomerular filtration rate.
Removal of mediators by extracorporeal treatment
Up to now, strategies to ameliorate inflammation in dialysis patients have been mostly limited to preventing induction of inflammatory mediators by the dialysis procedure. The use of pyrogen-free dialysate and biocompatible membranes may certainly be of benefit. An alternative approach is to lower plasma levels of mediators by the extracorporeal treatment, thus reducing inflammation and possibly cardiovascular mortality. How can this goal be achieved?
There are some obstacles to the efficient removal of cytokines.
However, most cytokines are eliminated by the kidneys [16,17] and in renal failure the half-life of cytokines may be significantly prolonged. For instance, the total body clearance of IL-10 in patients with chronic renal failure is only one third of the value in subjects with normal renal function [18]. Thus, in haemodialysis patients, extracorporeal removal may add substantially to total body clearance of cytokines. Moreover, new technologies enable the use of haemofiltration or haemodiafiltration employing ample convective transport with filtrate volumes of 68 l/h using on-line preparation of substitution fluids. In addition, large-pore membranes such as Diapes® (membrana GmbH, wuppertal, Germany) with molecular weight cut-offs beyond conventional high-flux membranes are now available that facilitate elimination of middle molecule-sized proteins.
Preliminary results indicate that large-pore membranes are superior to conventional low-flux, and even high-flux, membranes for cytokine elimination. We have demonstrated that there are differences between a conventional high-flux polysulfone membrane and Diapes® regarding their ability to remove cytokines from plasma in vitro [19]. The extent of cytokine elimination could not be predicted from its molecular weight. For instance, in the presence of convection, significantly higher amounts of IL-6 and TNF- were removed with Diapes® compared to conventional high-flux polysulfone membranes. Leptin and IL-10 were readily adsorbed to both high-flux membranes, while IL-1ß, IL-1 receptor antagonist and soluble TNF-receptors were equally well cleared by both high-flux membranes. Thus, the extent of elimination does not only depend on the molecular weight of the cytokine but rather on other properties such as charge, hydrophilicity or carrier binding. The extent of adsorption as well as of diffusive or convective transport must be determined experimentally for each cytokine and cannot be predicted a priori. For certain cytokines, superior removal by large-pore membranes with pore sizes above conventional high-flux dialysers can be expected.
Certainly, because of the non-specificity of extracorporeal treatments, other molecules in the range of middle molecules will be removed along with inflammatory mediators even though they are not necessarily harmful. Thus, investigators using large-pore membranes should watch carefully for possible clinical side effects. Moreover, up to now, the degree of albumin losses with large-pore membranes has not well investigated and should be monitored closely. However, advanced membrane technology will create membranes with even steeper molecular weight cut-offs, enabling removal of molecules in the range of middle molecules without, or at best with only modest, concurrent albumin losses.
Need for prospective studies
There is evidence from retrospective studies that the choice of membrane may be associated with better survival [20,21]. Recent data from the USRDS dialysis morbidity and mortality study in more than 12 000 patients confirmed the improved survival with the use of high-flux membranes. Among all membranes, mortality was lowest for patients treated with high-flux synthetic membranes [22]. Whether this effect is due to improved removal of mediators and amelioration of inflammation remains speculative. The hypothesis that dampening inflammation by removing circulating mediators will influence cardiovascular mortality may be rather simplistic. However, there is some evidence for an active role of mediators such as CRP in atherosclerosis because it is deposited in infarcted myocardium and atherosclerotic lesions, thereby promoting local complement activation, tissue damage and clotting by induction of tissue factor expression [23]. In addition, in the physicians' health study, the risk reduction of myocardial infarction associated with aspirin was greatest in those patients with the highest levels of CRP [2]. These results raise the possibility that modifying the inflammatory response may decrease cardiovascular mortality, and randomized trials employing the use of non-steroidal anti-inflammatory drugs to reduce cardiovascular events are currently being planned. Whether removal of cytokines by extracorporeal treatments will reduce the inflammatory response in haemodialysis patients has yet to be shown in clinical trials. Prospective studies aimed at examining the effect of high-flux or large-pore membranes on markers of inflammation as well as on cardiovascular morbidity and mortality are urgently required.
Notes
Correspondence and offprint requests to: Dr R. Schindler, Department of Nephrology and Intensive Care Medicine, Charit-Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany. Email: ralf.schindler{at}charite.de
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