(1)
Department of Cardiovascular, Neural and Metabolic Sciences, Istituto Auxologico Italiano, Milan, Italy
Life expectancy in patients with Chronic Kidney Disease (CKD) appears to be substantially reduced compared to the general population. As a matter of fact, it is well known that the high incidence of cardiovascular events heavily affects the prognosis in patients with renal disease. There is a close relationship between aortic stiffness and Chronic Kidney Disease, which is supported by a number of studies.
7.1 Vascular Calcifications and Arterial Stiffness
Several biological processes are involved in the progression of atherosclerosis and arteriosclerosis in patients with Chronic Kidney Disease. This disease is associated with accelerated vascular aging; activation of the renin–angiotensin system, aortic inflammation, and vascular metalloproteinase activity lead to changes in the extracellular matrix and to endothelial dysfunction, paving the way to arterial stiffening. Indeed, increased arterial stiffness is observed even in the early stages of Chronic Kidney Disease, suggesting that arterial remodeling occurs early in the course of the disease.
It is worth noting that arterial calcifications occur in Chronic Kidney Disease, and it is associated with increased morbidity and mortality. An inverse relationship between arterial calcifications and bone density has been documented in uremic patients. Disturbances of calcium and phosphate metabolism in Chronic Kidney Disease are associated with PTH secretion and uremic bone disease. Actually, in patients with Chronic Kidney Disease and end-stage renal disease (ESRD), the association between bone and vascular calcifications concerns both aspects of bone disorders: secondary hyperparathyroidism, characterized by high bone turnover, and low bone activity (adynamic bone disease). Even if in secondary hyperparathyroidism the increased bone resorption associated with endogenous release of phosphate and calcium could play a critical role in the induction of vascular calcification, all the same, in these patients, arterial calcifications are more frequently observed in patients with adynamic bone disease (ABD), characterized by a low-bone turnover without osteoid accumulation [1, 2]. The clinical link between mineral bone disorder (MBD) and vascular disease arising from primary perturbations in calcium phosphate homeostasis is clearly recognized. So that KGIDO (international group on Kidney Disease: Improving Global Outcomes) codified the clinical entity CKD-MBD, the mineral and bone disorder of Chronic Kidney Disease that encompasses the vascular calcification of Chronic Kidney Disease.
The presence and extent of arterial calcifications are independently predictive of subsequent cardiovascular disease and mortality beyond established conventional risk factors. Calcification develops in two distinct sites [3]: the intima and media layers of the arterial wall (Fig. 7.1).
Fig. 7.1
Arterial calcifications. (a) Atherosclerotic intimal calcifications: intimal calcification is associated with the development of plaques and occlusive lesions. (b) Arterial medial calcifications: calcifications involving the arterial medial layer cause alterations of the arterial wall viscoelastic properties but not a reduction in the arterial lumen
7.1.1 Arterial Intimal Calcification
Atherosclerotic intimal calcification is associated with the development of plaques and occlusive lesions. It is also associated with inflammatory process and with cholesterol depositions and usually contributes to stenotic lesions and occlusion of the artery. Intimal calcification is mainly found in the elderly and in patients with diabetes, who have a clinical history of atherosclerotic complications and is associated with lower serum albumin, elevated phosphate, and higher calcium carbonate intake.
7.1.2 Arterial Medial Calcification
Medial calcification (Mönckeberg medial calcific sclerosis) is characterized by concentric mineral deposits within the arterial middle layer (tunica media), initiating along mural elastin fibers. Calcifications in the arterial medial layer are frequently observed with aging in the general population; however, it is significantly more pronounced in patients with metabolic disorders, such as diabetes or Chronic Kidney Disease. Vascular calcification is often triggered by active processes involving inflammatory cytokines and metalloproteinases in the absence of atherosclerotic plaques. Actually, hyperparathyroidism and disordered calcium and phosphate metabolism, which are common features of advanced Chronic Kidney Disease, contribute to it.
Calcifications may be observed in the medial layer of the aorta and large elastic arteries, in medium-sized visceral and kidney arteries, as well as in coronary and other transitional arteries with diameter of at least 0.5 mm. A systemic distribution of vascular medial calcification appears to be uncommon.
While arterial intimal calcification appears to be associated with generalized atherosclerosis, which is not specifically attributable to hemodialysis, arterial medial calcification seems to be much more closely associated with hemodialysis treatment and its duration.
Until the late twentieth century, only intimal calcifications, associated with atherosclerosis, were considered at high risk for cardiovascular diseases. As a matter of fact, the cardiovascular risk was considered to be secondary to the reduction in the arterial lumen due to the atherothrombotic process. Vascular calcifications were considered to be a cardiovascular risk since they revealed the presence of atherosclerosis plaques. From a prognostic point of view, on the contrary, medial calcifications were considered less important. Actually, these were wrongly considered to be a low risk factor for cardiovascular disease, as their presence did not alter the size of the vascular lumen. However, epidemiological studies have shown that vascular calcifications, either intimal or medial, are associated with high cardiovascular mortality and morbidity. Therefore, the increase in the cardiovascular risk is not only associated with the degree of the reduction affecting the vascular lumen but also with increases in arterial stiffness. Medial calcification processes in the aorta and large arteries determine an alteration in arterial viscoelastic properties, causing arterial stiffness (Fig. 7.2).
