الفهرس 
CALCIUM METABOLISM IN NORMAL SUBJECTSOnly 14 pages are availabe for public view
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Abstract
Severe vascular calcification develops early and rapidly in hemodialysis patients. The precise etiology of vascular calcification and its relationship to renal bone disease is not known. However, our laboratory and others have presented abundant evidence indicating that vascular calcification is an active, cell-mediated process that parallels in many ways the process of skeletal mineralization, beginning with active initiation by apoptosis and vesicle release. Knockout studies and human single gene defects and polymorphisms have focused attention on potential regulatory proteins, many with a role in bone mineralization. Prominent among them are inhibitors of hydroxyapatite formation – MGP and fetuin-A – and regulators of bone cell differentiation such as OPG. These proteins undergo changes in expression in human calcified arteries and human VSMC cultures. These changes are suggestive of a disinhibition of vascular calcification and a phenotypic conversion of macrophages and VSMCs to cell types that actively regulate mineralization and reabsorption.
Although mineral imbalance is a crucial mechanism, there is converging evidence that there are additional factors involved during VSMC calcification in ESRD. Our theoretical model of vascular calcification proposes interplay of procalcifying and anticalcifying mechanisms, some of which are influenced by dietary and treatment mainstays for ESRD patients. Warfarin and vitamin D contribute to the process of soft tissue calcification while vitamin K increases the inhibitory capacity. Transcriptional regulation by Cbfa l and TGFβ-superfamily members of essential proteins such as MGP may contribute to phenotypic changes in VSMCs and, together with the loss of other serum/local inhibitory molecules, disinhibit pathophysiological soft tissue calcification.
The remarkably consistent co-occurrence of vascular calcification and osteoporosis is strongly suggestive of a relationship between bone mineralization and vascular calcification. Current research is exploring several theories, including the possibility of a common etiology involving oxidized lipids and inflammation, the influence of common regulatory molecules, and parathyroid-related changes in calcium load and bone turnover (Shanahan, 2005).
Emerging evidence suggests that endothelial dysfunction, oxidative stress, vascular calcification, and inflammation are strongly interrelated and together play a major role in the initiation and progression of vascular disease in CKD. Because the observed associations between a specific uremic phenotype and genetic polymorphisms should not be affected by the reverse epidemiology phenomenon, the Mendelian randomization approach (i.e., finding the links between randomly distributed genotypes and the uremic phenotype) may be a valid method to pinpoint the real cardiovascular risk factors in CKD. We also propose that future research protocols, whenever possible, should use a global approach by studying whole pathogenetic pathways rather than associative studies linking a single risk factor to morbidity and mortality. Mechanistic experimental and interventional studies designed to test whether biomarkers are not only markers but also etiological risk factors may provide further information that could lead to novel treatment options. As traditional and novel risk factors are not likely to operate in separate rigid compartments, experimental studies identifying the impact of traditional risk factors, such as hypertension, diabetes, and obesity, on the atherogenic potential of novel risk factors in the uremic milieu are needed. Finally, new areas of research that aim to use innovative tools, such as proteomics and epigenetics, may be helpful in the identification of new vascular markers or factors, unravel existing pathogenetic pathways, and facilitate the more rapid development of novel, safe, and effective therapies (Stenvinkel et al., 2007).