HYPERTONIA ÉS NEPHROLOGIA - eLitMed.hu

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ÖSSZEFOGLALÓ KÖZLEMÉNYEK / REVIEW ARTICLES Novel insights into uremic vascular calcifications Markus Ketteler, MD Department of Nephrology and Clinical Immunology. University Hospital Aachen, Germany HYPERTONIA ÉS NEPHROLOGIA 2005; 9 (1):14–18. ABSTRACT In the recent past, it has become increasingly clear that extracellular calcium and phosphate homeostasis is a tightly regulated process. Even the physiological serum concentrations of calcium and phosphate are several orders of magnitude above their solubility product in an aqueous solution. Although pH, body temperature and the ionic strength of serum compensates largely for this difference, serum remains a “metastable” solution concerning calcium and phosphate precipitation. Therefore, precipitation inhibitory mechanisms must be operative to prevent extraosseous calcification. In this context, a number of local and systemic calcification inhibitors could be identified in recent years, and deficiencies and dysregulations of such factors, respectively, may contribute to morbidity and even mortality in patient populations. Further, hyperphosphatemia may not just passively contribute to an increased calcium and phosphate ion product, but may induce an active process of osteogenic dedifferentiation in vascular smooth muscle cells. Extensive extraosseous calcifications occur with high prevalence in patients with end-stage renal disease (ESRD), and especially vascular manifestations are clearly associated with cardiovascular events and decreased survival in this particular patient group. In the context of the accelerated nature of atherosclerosis observed in dialysis patients, novel pathomechanisms involved in uremic vascular calcification will be discussed in this brief overview. Key words: vascular calcification, end stage renal disease, hyperphosphatemia, Matrix Gla Protein, Fetuin-A Corresponding author: PD Dr. med. Markus Ketteler Department of Nephrology and Clinical Immunology Universtity Hospital Aachen Pauwelsstr. 30 D-52057 Aachen Germany Phone: +49-241-8089530 Fax: +49-241-8082446 e-mail: mketteler@ukaachen.de Content Introduction Intimal versus medial calcifications The role of hyperphosphatemia Calcification inhibitors Matrix Gla Protein (MGP) Fetuin-A (2-Heremans Schmid glycoprotein, AHSG) Conclusion References INTRODUCTION Cardiovascular mortality is dramatically increased in uremic patients. Registry data demonstrated that this is particularly true for young ESRD patients: 30-year-old dialysis patients suffer from an up to 500-fold elevated mortality risk when compared to an age-matched normal population and have an average life expectancy comparable to 85-year-old non-dialysis subjects (1). Accelerated calcifying atherosclerosis and valvular calcifications are hallmarks of cardiovascular disease in the dialysis population, and the magnitude of vessel calcification was recently identified as an independent risk factor of cardiovascular death in dialysis patients (2, 3). Typical metabolic disturbances in uremia including hyperphosphatemia, an increased calcium x phosphate product, hyperparathyroidism, and possibly an increased calcium intake are independent predictors of cardiovascular morbidity and mortality in this population (4-7). By using EBCT, Goodman et al. demonstrated in young dialysis patients that coronary artery calcifications (see example in figure 1) are al-
2005; 9 (1):14–18. NOVEL INSIGHTS INTO UREMIC VASCULAR CALCIFICATIONS 15 Figure 1. Severely calcified coronary arteries in a 42-year-old male diaylsis ready highly prevalent at the age of 20–30 years and that the calcification burden can be directly related to hyperphosphatemia, an increased calcium x phosphate product and an increased calcium intake (7). Moreover, Oh and coworkers were able to demonstrate significant coronary artery calcifications in 92% of patients aged 19–39 years with childhood-onset chronic renal failure (8). In addition to a strong association between vascular calcification and time on dialysis and an increased calcium x phosphate product, respectively, the magnitude of calcification was strongly related to elevated CRP levels in this study, thus to a state of (micro-)inflammation (8). A correlation between coronary artery calcifications and elevated CRP levels was recently confirmed in the Framingham cohort, i.e. a non-uremic population, indicating that inflammatory processes are likely involved in the pathogenesis of vascular calcification (9). INTIMAL VERSUS MEDIAL CALCIFICATIONS There are two distinct types of arterial calcification (10,11). One affects the intimal layer of arteries and occurs within atherosclerotic plaques, the other involves the medial wall of arteries. This second type of vascular calcification is common in patients with CKD and those with diabetes mellitus, and it is unique to these two clinical disorders. The consequences of each form of arterial calcification differ fundamentally. The manifestations of atherosclerotic vascular disease are well established both in the general population and in those with CKD. Here, intimal lesions narrow the arterial lumen and can compromise blood flow leading to tissue ischemia. Ischemic events can occur acutely, however, in previously unobstructed vessels when atherosclerotic plaques rupture and initiate thrombus formation. Calcification is an integral part of the atherosclerotic process and occurs in up to 90% of atheromatous lesions (12). This strong association serves as the basis for using sensitive noninvasive radiographic methods such as EBCT to detect calcium deposits in the coronary arteries as an indicator of atherosclerotic burden in the general population (13-15). The calcium content of atherosclerotic lesions has been reported to be greater in patients on dialysis than in age-matched subjects with normal renal function (16). It is not clear whether this difference simply reflects the more extensive softtissue calcification common in CKD or disturbances in the regulation of atherosclerotic calcification, and whether the presence of rigid, friable calcium deposits contributes to plaque rupture and subsequent arterial thrombosis (17, 18). The hemodynamic consequences of medial wall calcification (Mönckeberg’s sclerosis) are quite different from those due to atherosclerotic plaque calcification (19). Mineral deposition occurs diffusely throughout the tunica media which is rich in elastic lamellae. Medial wall calcification increases vascular stiffness and reduces vascular compliance, changes that adversely affect the capacity of the arterial circulation to dampen increases in arterial pressure with each ventricular systole. As a result, systolic blood pressure rises, pulse pressure widens, and pulse wave velocity increases (19, 20). These hemodynamic alterations cause left ventricular hypertrophy, and they can compromise coronary artery blood flow during diastole. In adults with CKD, the extent of arterial calcification represents the aggregate of both atherosclerotic and medial wall calcification, and evidence of arterial calcification in adults with CKD is associated with adverse clinical outcomes, including myocardial infarction, congestive heart failure, endocarditis, valvular heart disease and death (21, 22). Survival among patients undergoing regular hemodialysis is inversely related to the extent of vascular calcification as measured by B-mode ultrasound (21). When present, arterial calcification progresses more rapidly, as judged by interval changes in coronary artery calcification scores measured by EBCT, in patients treated with dialysis than in subjects from the general population (7, 23). Such findings suggest but do not prove that medial wall calcification plays a dominant role in the progression of vascular calcification in patients with CKD. Progression rates are much lower, however, in persons who do not have CKD where interval changes in calcification scores presumably reflect the evolution of atherosclerotic calcification only (24). For patients with CKD who are treated with hemodialysis, the rate of progression of coronary artery and aortic calcification has been reported to be greater in those who use large oral doses of calcium-containing compounds rather than the calcium-free, phosphate-binding agent sevelamer (23). Although changes in lipid metabolism in those given sevelamer may contribute to such differences (25, 26), the results emphasize further the potentially critical link between disturbances in mineral metabolism and the progression of arterial calcification in patients with CKD. THE ROLE OF HYPERPHOSPHATEMIA Hyperphosphatemia was identified as an independent cardiovascular mortality risk factor in the dialysis population in three large registry studies (4-6). Since hyperphosphatemia contributes directly to an increased calcium x phosphate product and triggers secondary hyperparathyroidism, it was thought that high serum phosphate concentrations “passively” cause increased and progressive hydroxyapatite deposition in tissues and vessels. However, in vitro studies recently
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