A biomarker, osteoprotegerin, in patients undergoing hemodialysis.

See Article on Page 668-677

Despite progress in patient care and increased understanding of the pathophysiology, high morbidity and mortality rates have persisted in patients with end-stage renal disease (ESRD). This is primarily due to the high incidence of cardiovascular events in patients with ESRD, and many attempts have been made to try to increase survival and improve the quality of life of patients undergoing dialysis. Because of the severity of cardiovascular disease (CVD), which could manifest as sudden death, and the associated pathologies, efforts for disease prevention in high-risk populations are likely to be the most effective treatment strategy. However, in addition to traditional cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes mellitus, and obesity, nontraditional risk factors such as inf lammation, malnutrition, and chronic kidney disease-mineral bone disorder (CKD-MBD) also to contribute to CVD in patients undergoing dialysis. It is therefore challenging to identify high-risk patients. The measurement of vascular calcification and arterial stiffness is one way to identify patients susceptible to CVD. Several methods are used to quantify these parameters, including radiologic examinations such as plain radiography and computed tomography, or the measurement of pulse wave velocity. Although some studies demonstrated the usefulness of these traditional methods for identifying individuals at risk of developing CVD, they are not considered sufficient to accurately estimate risk, due to their relatively low sensitivity and specificity.

The measurement of biomarker in blood related to atherosclerosis or vascular calcification to predict cardiovascular events has gained interest for reasons of convenience. However, this only has real diagnostic value if the biomarkers are accurately validated. The identif ication of biomarkers could also provide insight into disease pathogenesis, which is fundamental for the development of targeted therapies. In addition to C-reactive protein and low density lipoprotein cholesterol, which are accepted as cardiovascular risk factors, other markers, including natriuretic peptide, apolipoprotein, homocysteine, and troponin I, are correlated with cardiovascular events in the general population. However, due to the complexity of the pathophysiology of CVD in patients undergoing dialysis, none of these have been accepted as useful biomarkers to predict CVD in these individuals.

Osteoprotegerin (OPG) is a cytokine that belongs to the tumor necrosis factor receptor superfamily. It is produced by osteoblasts, endothelial cells, and vascular smooth muscle cells [1]. OPG interferes with binding of the receptor activator for nuclear factor-κB ligand (RANKL) to its cell surface receptor by functioning as a decoy receptor, thus inhibiting the differentiation and activity of osteoclasts [2]. In bone, OPG has an antiosteoclastic effect because it regulates bone resorption [3]. Although the actions of OPG in the vasculature and heart are not fully understood, increased expression of OPG and RANKL occur in atherosclerotic lesions, which promotes vascular calcification [4]. As reported by Lee et al. [5] in the current issue, recent epidemiological studies have suggested a predictive role of serum OPG in coronary calcification and cardiovascular mortality, both in predialysis patients, and in patients treated with hemodialysis and peritoneal dialysis [6-10]. Most studies suggested that higher OPG levels were associated with advanced vascular calcification and arterial stiffness. In addition to its role in vascular calcification, OPG contributes to the development of CVD by modulating inflammation and endothelial dysfunction [6]. However, the exact role of OPG in atherosclerosis remains unclear. Interestingly, OPG-deficient mice displayed calcified arterioles [11], and treatment with OPG attenuated aortic valve calcification [12]. The detailed mechanism for these effects is yet to be elucidated, and should be studied further.

Given that OPG originates in bone, it may link CKD-MBD with the progression of CVD. Recent studies revealed that serum OPG levels increased concurrently with CKD progression, which was positively correlated with fibroblast growth factor-23 [8], but negatively correlated with bone mineral density (BMD) [13]. This suggests a potential role for OPG in CKD-MBD. Because OPG would be expected to exert a protective effect on BMD, it is likely that the increase in circulating OPG is a compensatory response. However, the interaction between OPG and additional factors in bone metabolism requires further investigation.

Although it would be premature to conclude that OPG is a reliable early biomarker for the prediction of cardiovascular events in dialysis patients, it may be useful to classify at risk patients, particularly when combined with an additional modality for risk stratification. For OPG to be validated as a biomarker, future studies should apply prospective screening to a large cohort of patients. In addition, OPG could be tested in randomized controlled trials to assess whether it has therapeutic potential. Moreover, studies should be conducted to identify confirmatory diagnostic protocols for detecting cardiovascular events as early as possible. This will also help bring new developments to the care of patients undergoing dialysis.