Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: how do new pieces fit into the uremic puzzle?

Abstract

Premature cardiovascular disease (CVD), including stroke, peripheral vascular disease, sudden death, coronary artery disease, and congestive heart failure, is a notorious problem in patients with chronic kidney disease (CKD). Because the presence of CVD is independently associated with kidney function decline, it appears that the relationship between CKD and CVD is reciprocal or bidirectional, and that it is this association that leads to the vicious circle contributing to premature death. As randomized, placebo-controlled trials have so far been disappointing and unable to show a survival benefit of various treatment strategies, such a lipid-lowering, increased dialysis dose and normalization of hemoglobin, the risk factor profile seems to be different in CKD compared with the general population. Indeed, seemingly paradoxical associations between traditional risk factors and cardiovascular outcome in patients with advanced CKD have complicated our efforts to identify the real cardiovascular culprits. This review focuses on the many new pieces that need to be fit into the complicated puzzle of uremic vascular disease, including persistent inflammation, endothelial dysfunction, oxidative stress, and vascular ossification. Each of these is not only highly prevalent in CKD but also more strongly linked to CVD in these patients than in the general population. However, a causal relationship between these new markers and CVD in CKD patients remains to be established. Finally, two novel disciplines, proteomics and epigenetics, will be discussed, because these tools may be helpful in the understanding of the discussed vascular risk factors.

Figure 1.

Schematic presentation of traditional and novel (or uremia-specific) cardiovascular risk factors in chronic kidney disease.

Figure 2.

The complicated puzzle of uremic CVD. Red puzzle pieces depict traditional (i.e., Framingham) risk factors thought to contribute to an excessive cardiovascular risk in CKD. The fact that many pieces in the puzzle are false (i.e., some pieces are risk markers and not etiological cardiovascular risk factors) renders the possibility to solve it more difficult. Blue puzzle pieces depict some inflammatory biomarkers that have been demonstrated to be associated with poor outcome in CKD. Green puzzle pieces depict some risk markers associated with endothelial dysfunction. Orange puzzle pieces depict risk markers associated with vascular ossification. Brown puzzle pieces depict surrogate markers of oxidative stress that have been associated with cardiovascular outcome in CKD. Purple puzzle pieces depict the emerging role of adipokines in uremic CVD. Gray puzzle pieces depict other risk markers associated with CVD in uremia, such as markers associated with volume overload, protein-energy wasting, and sympathetic overactivation. Finally, white puzzle pieces displayed outside the heart depict some emerging risk markers that may be associated with uremic CVD. CVD, cardiovascular disease; CKD, chronic kidney disease; CRP, C-reactive protein; sVCAM, soluble vascular cell adhesion molecule; SNP, single nucleotide polymorphism; T3, triiodothyronine; PTX3, pentraxin-3; ADMA, asymmetric dimethylarginine; AGEs, advanced glycation end products; OPN, osteopontin; PTH, parathyroid hormone; MPO, myeloperoxidase; oxLDL, oxidized LDL; OPG, osteoprotegerin; NT-pro-BNP, N-terminal pro-brain natriuretic peptide.

Figure 3.

Schematic presentation of oxidation and antioxidant pathways in chronic kidney disease. NADPH, nicotinamideadenine dinucleotide phosphate; SOD, superoxide dismutase; NOS, nitric oxide synthase; CytP450, cytochromes P450; GSH, reduced glutathione; GSSG, oxidized glutathione; GSH-PX, glutathione peroxidase.

Figure 4.

Schematic presentation of environmental causes of epigenetic modifications, including potential uremic insults, which may result in defective gene stability or expression.