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NDT Advance Access originally published online on July 22, 2006
Nephrology Dialysis Transplantation 2006 21(10):2718-2720; doi:10.1093/ndt/gfl317
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

C-reactive protein—does it promote vascular disease?*

Peter Stenvinkel

Division of Renal Medicine, Department of Clinical Science Intervention and Technology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

Correspondence and offprint requests to: Peter Stenvinkel, MD, PhD, Department of Renal Medicine K56, Karolinska Institutet, Karolinska University Hospital at Huddinge.Email: peter.stenvinkel{at}ki.se

Keywords: atherosclerosis; chronic kidney disease; CRP; genetics; interleukin-6

Although some in vitro data support a direct role for C-reactive protein (CRP) in atherogenesis, there is as yet no definite evidence that CRP per se mediates atherogenesis in vivo. Whereas a recent study demonstrates that a specific binder of human CRP has cardioprotective effects in rats, studies in non-renal patients, using the Mendelian approach, suggest that CRP is not a suitable target for direct intervention. Thus, additional studies evaluating genotype (or haplotype) and vascular events are needed to clarify whether the link between elevated CRP and vascular events in numerous observational studies of chronic kidney disease (CKD) patients is causal or confounded. The availability of a specific CRP binder may be yet another tool to determine whether CRP contributes directly to atherogenesis in humans or if this protein is just an innocent bystander, and pro-atherogenic cytokines the real villains.

To improve the abysmal survival rate in CKD, nephrologists must identify which risk factor(s) associated with uraemia best explain why there is such a discrepancy between the vascular and chronological age in this patient group. Among several novel risk factors, persistent inflammation, usually recognized by elevated serum levels of CRP, has attracted much interest. According to the inflammation hypothesis of atherosclerosis proposed by Ross [1], local inflammatory stimuli, such as oxidatively modified products, advanced glycation endproducts or various persistent infectious processes, may change the milieu of the arterial wall. This may promote the production of pro-atherogenic adhesion molecules and growth factors, which play important roles in the atherogenic process. However, although the notion that inflammation plays a central role in the pathophysiology of atherosclerosis has gathered momentum in vascular research, we do not know yet whether an elevation of CRP is just a reflection of vascular injury or a promoter.

As CRP is present in atherosclerotic plaques, binds to modified low-density lipoprotein and activates the classical complement pathway, it has been suggested that CRP mediates vascular disease [2]. Indeed, in vitro data have shown that CRP has pro-inflammatory and pro-thrombotic effects [3]. Moreover, human CRP has been shown to contribute to ischaemic tissue damage in both the brain and heart of adult rats [4]. Other documented effects of CRP include inhibition of endothelial progenitor cell differentiation and function [5] and up-regulation of angiotensin type-1 receptors [6]. However, most of the published studies have used commercially purchased CRP and few report any controls to establish whether results obtained are attributable to CRP itself or a bacterial contamination [7]. Despite the numerous reports of potential pro-atherogenic properties of CRP in vitro, the evidence that CRP promotes atherosclerosis in vivo is controversial. Whereas one study in apoE-deficient mice showed that human transgene expression caused accelerated aortic atherosclerosis [8], another showed that human transgenic CRP is neither pro-atherogenic nor pro-thrombotic in apoE-deficient mice [9]. Indeed, because any inflammatory stimuli that would prompt the release of pro-atherogenic cytokines, such as interleukin-1 (IL-1), IL-6 and tumour necrosis factor-{alpha}, also stimulate hepatic CRP production, it has been argued that the association between vascular damage and CRP may be indirect and that other inflammatory mediators are the main culprits [10]. In fact, as there is no known CRP-deficient condition in humans, Schwedler et al. [11] suggested that CRP is not only a ‘bad guy’ but also has survival value [11]. It is possible that some of the contradictory results reported in the literature may be attributed to the fact that CRP exists in two distinct forms (i) native pentameric CRP (nCRP) detectable in serum with both pro-and anti-inflammatory effects and (ii) the tissue-bound form-modified or monomeric CRP (mCRP), with predominantly pro-inflammatory effects [11]. As the dissociation between nCRP and mCRP may be affected by several alterations caused by uraemia, such as disturbances in pH, urea and calcium homeostasis, the atherogenic potential of CRP may be different in CKD.

Since the administration of human CRP to rats is such an excellent model to study the actions of endogenous human CRP [4], the recent study by Pepys et al. [12] on the design, synthesis and efficacy of a specific small-molecule inhibitor of CRP, 1,6-bis(phosphocholine)-hexane, is of major interest. Five molecules of this compound are bound to two pentameric CRP molecules blocking its function [12]. Whereas administration of human CRP was associated with increased mortality and infarct size in rats undergoing coronary artery ligation, no deaths and an infarct size comparable to vehicle-treated rats were observed in rats pre-treated with this CRP binder [12]. Potential applications may include any inflammatory and/or infective conditions in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury [12]. Thus, considering the high prevalence of elevated CRP in European [13] and North-American [14] CKD populations, therapeutic CRP inhibition may be a new approach to prevent cardiovascular complications in this patient group.

There is evidence of a substantial heritability for CRP levels [15] and individual factors significantly influence the levels of inflammatory markers in CKD. Thus, several candidate genes may affect the prevalence of inflammation in this patient group, which in turn may affect the risk of vascular complications and outcome. Indeed, recent developments in the field of genetics have opened up entirely new possibilities to understand the impact of genotype on disease development and progress. This will offer new options and treatment strategies. The identification of genetic variations in genes related to the inflammation axis, in individuals more susceptible to chronic inflammation, might be an interesting approach for tracking CKD patients at high risk who may benefit from more aggressive treatment. As observed epidemiological associations between CRP and health outcomes might be affected by reverse causation or confounding, the Mendelian randomization approach (Figure 1) has recently been used to gain insight into the true nature of the CRP vascular disease association [16]. Casas et al. [17] demonstrated that although a common CRP polymorphism is associated with important differences in CRP concentrations, there was no association with the genotype and coronary events. In accordance, the recent Rotterdam study [18] suggest that common variations in the CRP gene does not have any effect on coronary heart disease occurence. Moreover, by the same approach, others found that whereas CRP polymorphisms were associated with robust differences in CRP levels there was no evidence that CRP is causal in the pathology of either the metabolic syndrome [18] or hypertension [19].


Figure 1
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  		Fig. 1. In both non-renal and renal patient populations strong associations are observed between CRP and cardiovascular disease and its risk factors. However, these epidemiological associations might be affected by reverse causation or confounding. By using the Mendelian randomization approach, the confounding effects of environmental exposure might be overcome, since the association between a disease and a specific gene polymorphism is not generally susceptible to reverse causation or confounding [16]. Of note, the Mendelian randomization approach is similar to the technique used in randomized trial association studies [16]. As recent studies have demonstrated robust associations between CRP gene polymorphisms and circulating CRP concentrations, but failed to find associations between CRP haplotypes or genotypes and vascular disease phenotypes, these studies suggest that CRP is not a suitable target for direct therapeutic intervention [17–20].

 
In summary, it is exciting that a specific binder of human CRP seems to have cardioprotective effects in rats. However, as studies using the paradigm of Mendelian randomization show that CRP is not a suitable target for intervention, further studies are needed to resolve the clinically important question of whether or not CRP promotes vascular disease.

Conflict of interest statement. None declared.



   Notes
 
* Comment on Pepys MB, Hirschfield GM, Tennent GA et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 2006; 440: 1217–1221 Back



   References
Top
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Received for publication: 2. 5.06
Accepted in revised form: 5. 5.06


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