In the clinical setting, C-reactive protein (CRP) is the molecule that is most often used as a marker to monitor inflammation. Synthesis of CRP in the liver occurs during a wide range of acute and chronic inflammatory conditions, but also in malignancies or tissue injuries. With its 19-h half-life, CRP is easy to detect in the circulation. The average CRP level ranges from 1 to 3 mg/l in the general adult population [20] while it is typically twice as high in dialysis patients [21, 22]. Similarly, patients with CKD not yet on dialysis display CRP concentrations higher than those observed in the general population and the probability of having an increased CRP rises as GFR decreases [9]. The exact mechanisms that lead to increase in CRP are still not clear. However, apart from well-established clinical causes such as intercurrent illnesses, especially infections, the most probable factors responsible include: retention of circulating cytokines, advanced glycation end-products (AGEs), pro-oxidants, sympathetic overactivity, and the impact of the dialysis procedure itself [23–25].

Studies in vitro suggest that CRP is involved in vascular processes contributing to atherosclerosis. CRP is found in lipid-laden plaques [26] where its ability to facilitate monocyte adhesion has been documented [27]. Moreover, CRP inhibits endothelial nitric oxide synthase, and, hence, impairs vasoreactivity [28]. The concept that inflammation in general, and/or specifically the CRP may contribute to vascular risk was further strengthened by the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) [29]. In this trial, decrease in hsCRP following rosuvastatin administration was associated with a substantially lower cardiovascular risk, even though cholesterol concentration was normal in the studied subjects.

However, a growing body of evidence seems to negate a causative role of CRP in vascular pathology [30]. Experimental animals overexpressing CRP do not show features of accelerated atherosclerosis [31, 32]. Similarly, injections of large doses of CRP have no or minimal effect on atherosclerosis progression [33]. In the general population, large-scale Mendelian randomization studies have demonstrated that even marked elevations in CRP concentrations do not increase the risk of cardiovascular disease (CVD) [34, 35]. Similarly, there was no association between CRP haplotypes and cardiovascular risk in dialysis patients [36]. On the basis of these and other studies, CRP is currently regarded as a risk marker but not a risk factor for CVD.

Intereleukin-6 (IL-6) is a 24.5 kDa molecule that promotes the activation and proliferation of lymphocytes, differentiation of B cells, leukocyte recruitment, and the induction of the acute phase protein response in the liver [23]. The concentration of IL-6, one of the most potent drivers of CRP production, is typically elevated in CKD [37]. The mechanisms for IL-6 increase in the course of CKD are far from being clarified but the most probable are similar to the ones responsible for CRP elevation described above. The concentration of IL-6 has been shown to independently predict cardiovascular complications and mortality both in the general population [38] and in CKD patients [39, 40]. Several mechanisms by which IL-6 could influence the vascular system have been put forward such as an increase in platelet count, impaired insulin sensitivity, increased fibrinogen synthesis, and release of adhesion molecules in the endothelium [41]. It has been postulated that the potential role of Chlamydia pneumonia on atherosclerosis progression is mediated by increased IL-6 synthesis [42]. Indeed, CKD patients in whom atherosclerosis progresses show increased prevalence of anti-chlamydia antibodies, and, at the same time, enhanced IL-6 concentration, which independently predicts atherosclerosis progression (Fig. 6.1) [43]. A direct role for IL-6 in vascular complications is further strengthened by Mendelian randomization studies showing that functional variants of IL-6 gene affect the risk of CVD, both in the general population [44] and in CKD [45]. These results support a causative role of IL-6 in atherosclerosis progression and suggest it might be a target for future interventional studies.

Adipokines are a group of bioactive proteins, such as leptin, adiponectin and resistin that are synthesized and released by adipocytes. They are believed to mediate the well-established association between obesity and increased cardiovascular risk. Their concentration in CKD it typically increased, possibly due, at least in part, to impaired renal clearance [46]. Experimental studies have documented the presence of adipokine receptors in atherosclerotic plaques. Moreover, their role in sympathetic nerve activity, endothelial dysfunction, platelet aggregation and vascular smooth muscle cell proliferation has been postulated [46]. As clinical studies evaluating the abovementioned associations have brought conflicting results [46] more studies are needed to establish whether adipokines could be considered as true risk factors for CVD.

Oxidative stress can be defined as an imbalance between the generation of free radicals and the anti-oxidative capacity of surrounding tissues. Oxidative stress results in oxidation of macromolecules, including proteins, lipids, and carbohydrates, and is a widely acknowledged contributor to vascular disease in the general population. It is also an important feature of CKD, as increased levels of oxidative stress markers have been constantly demonstrated in uremic plasma [57]. Actually, oxidative stress starts early with renal function decline, and increased levels of oxidative markers have been documented already in CKD stage 3 [58]. Low-density lipoproteins (LDL) tend to be smaller and more dense in the course of CKD, and as such are more prone to oxidative modifications [59]. Indeed, numerous studies have shown that CKD, both at early stages and when dialysis-dependent, is associated with lipid and lipoprotein peroxidation [57]. Similarly, oxidatively modified plasma proteins and amino acids have also been documented in renal patients [57]. The exact mechanisms for oxidative stress in CKD are still poorly understood but are definitely associated with inflammation and PEW. As both these processes are prevalent in CKD, leading to hypoalbuminemia, it should be stated that the most important antioxidant capacity in plasma is provided by the thiol groups, which are largely located on the albumin molecule [57]. Therefore, patients with inflammation and/or PEW have a significantly diminished plasma antioxidant capacity. Other factors potentially responsible for increased oxidative stress in CKD have also been described (Fig. 6.2) [60]. Moreover, the uremic toxemia per se is postulated to augment oxidative stress, and, on the other hand, oxidative modifications of retained uremic solutes may potentiate their pathogenicity [57, 61]. As an example, recent evidence shows that HDL-cholesterol (regarded as anti-atherogenic) is transformed by symmetric dimethylarginine in the uremic milieu and paradoxically induces endothelial dysfunction via activation of toll-like receptor-2 [62]. In the clinical setting, few studies in CKD patients demonstrate associations between the intensity of oxidative stress and cardiovascular outcome [7, 63]. The impact of oxidative stress on hypertension and anemia, acknowledged cardiovascular risk factors, has also been postulated in CKD [64, 65]. Moreover, functional polymorphisms in genes encoding proteins involved in the antioxidant capacity have been shown to be associated with atherosclerosis, pointing to a casual role of oxidative stress in vascular complications in CKD [66, 67].

The close relationships between inflammation, oxidative stress and atherosclerosis have led to studies evaluating drugs that would target inflammation and oxidative stress to diminish the cardiovascular risk. The current strategies are described below and summarized in Table 6.2. However, since inflammation and oxidative stress in CKD are driven by numerous factors, it has to be stated that we may never find a single silver bullet to tame these disorders. Instead, we may need a holistic approach involving among others: adequate dialysis prescription, use of biocompatible membranes and solutions, avoidance of central dialysis catheters, exercise implementation, adequate nutrition, efficient treatment of co-morbidities, and perhaps, on top of that, targeted anti-inflammatory and anti-oxidative medications.