Update on interleukin-6 and its role in chronic renal failure

Roberto Pecoits-Filho, Bengt Lindholm, Jonas Axelsson and Peter Stenvinkel

Division of Nephrology and Baxter Novum, Department of Clinical Science, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden

Keywords: atherosclerosis; chronic renal failure; inflammation; interleukin-6; malnutrition; mortality

Introduction

Although a number of pro-inflammatory [such as tumour necrosis factor (TNF)-{alpha} and interleukin (IL)-1] and anti-inflammatory (such as IL-10) cytokines orchestrate the inflammatory response, available data suggest that IL-6 and its soluble receptor (sIL-6R) are central regulators of the inflammatory process [1]. The IL-6 system promotes inflammatory events through the activation and proliferation of lymphocytes, differentiation of B cells, leukocyte recruitment and the induction of the acute-phase protein response in the liver [2]. Chronic inflammation is increasingly recognized as an important issue due to its role in various pathological states, such as cardiovascular disease, obesity, diabetes, cancer and malnutrition [2]. Significant epidemiological information has recently linked plasma IL-6 to cardiovascular morbidity and mortality in non-renal patient groups [3]. Also, in end-stage renal disease (ESRD) patients an elevated IL-6 level is a strong predictor of poor outcome [4].

IL-6 is a 22–27 kDa polypeptide secreted from activated monocytes, macrophages, fibroblasts, adipocytes and endothelial cells in response to various stimuli, such as TNF-{alpha}, IL-1ß, bacterial endotoxins, physical exercise and oxidative stress (Figure 1Go). It is notable that whereas most other cytokines function via paracrine/autocrine mechanisms, the major effects of IL-6 are a consequence of its concentration in the circulation and can take place at sites distinct and far from its origin. Circulating IL-6 can be detected in healthy individuals in the 1 pg/ml range and it is markedly elevated in most, but not all, ESRD patients [5]. IL-6 exhibits its action via a receptor complex consisting of a specific IL-6 receptor and a signal-transducing subunit (gp130). The soluble forms of both receptor components are generated by shedding; these forms then reach the circulation and regulate the IL-6 activity. While sIL-6R binds to IL-6 in plasma, expanding the IL-6/sIL-6R half-life and extending the IL-6 bio-activity to organs containing the gp130 membrane-binding site [1], circulating gp130 acts as an antagonist of IL-6 biological functions, namely the activation of the acute-phase response, decrease in appetite, hypercatabolism, hypercoagulability and accelerated atherosclerosis [2]. Moreover, it was recently demonstrated that sIL-6R provides an important signalling pathway intimately involved in the transition between the early and late phase of the inflammatory response [1].



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Fig. 1.  Schematic view of IL-6 stimulation in chronic renal failure, from causative factors related to uraemia, activation of nuclear factors that trigger the transcription of inflammatory related proteins generating increased plasma IL-6, which will perform its biological functions according to the regulation of soluble receptors. AGE, advanced glycation end-products; LPS, lipopolysaccharide; NF{kappa}B, nuclear factor kappa B; IL-6 NF, interleukin-6 nuclear factor.

 

Causes of elevated IL-6 in ESRD

The potential causes of elevated plasma IL-6 levels in ESRD patients may be related to (i) the loss of kidney function, (ii) uraemia per se (and its sequelae, such as fluid overload, oxidative stress and susceptibility to infections) and (iii) dialysis-related factors (Figure 1Go). Even before the initiation of dialysis therapy, patients with decreased renal function already demonstrate signs of inflammation and the deterioration of renal function has been associated with a significant increase in serum cytokine levels [6]. Bolton et al. [7], in a multiple regression analysis, found that serum creatinine was the sole identified determinant of IL-6 levels in a group of pre-dialysis and dialysis patients. One explanation for these findings might be the impairment of renal clearance or inactivation of IL-6. Indeed, ESRD patients have lower urinary IL-6 receptor excretion than controls [8]. We recently described links between the IL-6 system and the residual renal function, showing an association between sIL-6R and the progression rate of renal function in the pre-dialysis phase, as well as an association between changes in glomerular filtration rate and changes in IL-6 during peritoneal dialysis (PD) treatment [9]. On the other hand, worsening of fluid overload and congestive heart failure may also contribute to increased IL-6 as renal function declines. The circulating levels of IL-6 are increased in patients with chronic heart failure and both local and systemic effects of pro-inflammatory cytokines may be involved in the pathogenesis of heart failure [10]. Increased levels of IL-6 and C-reactive protein occur mainly in patients with decompensated congestive heart failure [11].

Additionally, a significant graded relationship between blood pressure and plasma levels of IL-6 [12] were observed in apparently healthy subjects. Based on these observations and the documented high prevalence of hypertension in ESRD, it could be speculated that poor blood pressure control might also stimulate IL-6 production. Although cumulative data suggest that various persistent infections, such as Chlamydia pneumoniae, are associated with atherosclerosis, the mechanisms behind this association remain unclear. However, as it was recently demonstrated that the acellular components of C.pneumoniae are potent stimuli for IL-6 production [13], this may be one mechanism by which chlamydial infection causes atherosclerosis. This hypothesis is supported by a recent clinical study, which showed an association between serological evidence of persistent chlamydial infection, carotid atherosclerosis and elevated IL-6 levels in ESRD patients [14]. Several genetic variations associated with plasma levels or expression in HeLa cells transiently transfected have been identified within the IL-6 gene promoter region, such as the -174G/C single nucleotide polymorphism (SNP). Although this SNP was associated with longevity in non-uraemic patients [15], we (unpublished data) could not find associations between the genotype and IL-6 plasma levels nor cardiovascular disease, malnutrition and outcome in ESRD patients.

Although the potential impact of the initiation of dialysis treatment on systemic inflammation has not yet been addressed appropriately, the dialysis procedure may result in additional stimulation of the inflammatory response. Indeed, Takahashi et al. [16] demonstrated that both haemodialysis (HD) and PD result in increased blood mononuclear cell IL-6 mRNA expression and plasma IL-6 levels. Several factors related to HD have been proposed as contributing to the generation of IL-6 and/or enhancing the inflammatory effect of IL-6; dialysis against bioincompatible membrane [8], the use of non-sterile dialysate [17] and backfiltration [18]. Caglar et al. [19] recently showed that while the increase in IL-6 concentration was modest during the HD session, levels further increased at the end of the 2 h post-HD period, providing clear evidence of a HD-induced delayed inflammatory response.

Clinical consequences of elevated IL-6 levels

The current understanding of atherosclerosis is that an inflammatory process involving the acute-phase response, such as infection, tissue injury or immune disturbance, is a primary event [20]. A recent study showing that injection of recombinant IL-6 exacerbates early atherosclerosis in apoE-deficient mice [21] suggests a possible role of IL-6 in this process. Indeed, several lines of evidence suggest that IL-6 is a significant pro-atherogenic cytokine. First, elevated levels of IL-6 are a primary stimulant of soluble intracellular adhesion molecule-1 (sICAM-1), which mediates the attachment and migration of leukocytes across the endothelial surface [22]. Second, IL-6 may contribute to the development of atherosclerosis through various metabolic, endothelial and coagulant mechanisms [23]. Further support for the concept that IL-6 may be more than just a marker of atherosclerosis can be derived from a recent study showing that increased IL-6 expression is involved at the fibrous plaque stage of the atherosclerotic process [24]. Finally, elevated circulating IL-6 levels were independently associated with progressive carotid atherosclerosis during the first 12 months of dialysis treatment [14].

Disturbances in protein and energy metabolism, hormonal derangements and a spontaneous reduction in dietary energy and protein intake may be responsible for the decline in nutritional status with progressive renal failure. IL-6 appears to be closely related to the control of body composition, since IL-6 is expressed both in adipose tissue and centrally in hypothalamic nuclei that regulate body composition. IL-6 deficient mice develop obesity and intracerebral, but not intraperitoneal, IL-6 treatment increased energy expenditure [25]. In elderly non-renal patients, cachexia is usually associated with above normal plasma concentrations of IL-6 [26]. Also, an important role for IL-6 in cachexia could be proposed as it stimulates the breakdown of muscle protein [27] and promotes cancer-related wasting [28]. Moreover, the IL-6 receptor antibody inhibits muscle atrophy in IL-6 transgenic mice [29]. In clinical studies, increased levels of IL-6 predict hypoalbuminaemia and are associated with various markers of malnutrition in cross-sectional analyses [5]. Although pro-inflammatory cytokines may predominantly cause malnutrition by increased protein catabolism, they also affect appetite and eating behaviour. The mechanism(s) of cytokine-induced anorexia are not clear, although some studies suggest a role of elevated leptin. Grunfeld et al. [30] found that administration of cytokines increased leptin mRNA levels in hamsters and noted a strong inverse correlation between leptin mRNA expression and subsequent food intake. Unfortunately, available data regarding the association between inflammation and leptin are conflicting in ESRD. While we [31] have presented data showing a weak, but significant, positive relation between IL-6 and serum leptin in HD patients, Don et al. [32] demonstrated that leptin levels might actually be suppressed during inflammation. Additionally, increased serum levels of IL-6 may be associated with changes in bone remodelling in ESRD patients. Indeed, a recent study shows that calcitriol treatment has an effect on bone remodelling by influencing the levels of plasma IL-6, beyond its suppressive effect on parathyroid hormone [33]. Finally, inflammation as such may be an important pathophysiological factor in primary renal disease and its progression towards ESRD; the specific role of IL-6 in this context is, however, not clear.

Conclusions

IL-6, the major mediator of the acute-phase response, is elevated in the plasma of ESRD patients and is a strong predictor of outcome. A number of factors prevalent in patients with ESRD, such as hypertension, adiposity, insulin resistance, fluid overload and persistent infections, could all be associated with elevated IL-6 levels. In addition, reduced renal function, directly or indirectly, seems to be closely related to IL-6 elevation and genetic variations may be of importance. However, also factors associated with the dialysis procedure, such as bioincompatibility of dialyser membranes and dialysis solutions, may stimulate IL-6 production. The clinical consequences of elevated IL-6 levels and strategies to reduce IL-6 levels should be further evaluated to confirm the importance of this cytokine as a central regulator of the inflammatory response in ESRD.

Acknowledgments

Baxter Healthcare and the Swedish Medical Research Foundation (P.S.) supported the present work.

Notes

Correspondence and offprint requests to: Peter Stenvinkel, MD, Department of Renal Medicine K56, Karolinska Institutet, Huddinge University Hospital, S-141 86 Stockholm, Sweden. Email: peter.stenvinkel{at}klinvet.ki.se Back

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