*3.1.2 Large-vessel calcification*

Calcification of aorta and other large arteries is associated with increased arterial stiffness. This will cause lack of distensibility, leading to hypertension and increased pulse pressure, both risk factors for left ventricular dysfunction and heart failure among CKD patients [85, 88].

#### **3.2 Risk factors**

The higher prevalence of traditional CV risk factors, such as older age, hypertension, dyslipidemia and diabetes, and the presence of nontraditional CV risk factors related to CKD (anemia, abnormal calcium and phosphate metabolism, extracellular fluid volume overload, electrolyte imbalance) may explain the high occurrence of CVD and contribute to intimal or medial wall calcification in patients with kidney failure [28].

#### *3.2.1 Demographic features and time on dialysis*

Vascular calcification is associated with the increasing age and time on dialysis [21, 89, 90]. A study with 134 patients on HD, peritoneal dialysis and with stage 4 CKD demonstrated that age and male gender were important determinants of VC [77, 91].

#### *3.2.2 Mineral metabolism*

Disorders of mineral metabolism may promote CV calcification, contributing to higher CVD and mortality in patients with kidney failure or ESRD. Several observational studies have noted an association between mineral and bone disorders with adverse outcomes, most notably with increased phosphate levels (increased risk of VC, cardiomyopathy, and mortality) [11, 22, 92, 93].

Hyperphosphatemia, uremia, hyperglycemia and other metabolites may initiate the process of VC by transforming vascular smooth muscle cells to a chondrocyte or osteoblast-like cell. In dialysis patients, this process is accelerated in the setting of the common presence of high calcium, high phosphorus, and abnormal bone remodeling [91].

#### *3.2.2.1 Hyperphosphatemia and hypercalcemia*

Epidemiological studies have shown that hyperphosphatemia is associated with unexpectedly high rates of CV events and death in ESRD patients [94].

Hyperphosphatemia is a strong inducer of VC by inducing smooth muscle cells to undergo an osteochondrogenic phenotype change through a mechanism requiring sodium-dependent phosphate cotransporters [11]. In a group of 43 patients receiving peritoneal dialysis studied by MDCT at baseline and after 1 year of followup, Stompor and colleagues reported a significant correlation between changes in coronary calcium score and mean values of phosphate and calcium–phosphate product [95]. A study with uremic rats fed with high phosphate diet showed that aortic medial calcification could be blocked by treatment with the phosphate binder, sevelamer [96].

Lowering serum phosphate levels with a non-calcium containing phosphate binder slows progression of VC in pre-dialysis and ESRD patients [97–99]. In predialysis patients, treatment with calcium carbonate did not enhance the progression of CAC, as it has been observed in patients on dialysis [97].

#### *3.2.2.2 Oral calcium intake*

In dialysis patients, the use of calcium-based phosphate binders is strongly associated with development and progression of CAC, due to the ingestion of large amounts of calcium and the consequent hypercalcemia [97]. Therefore, a positive calcium balance may increase the risk of calcium overload and CV calcification and it should be taken into account when calcium salts are prescribed. Discontinuation or dose reduction of calcium-based phosphate binders is suggested in the presence of hypercalcemia, CV calcification, adynamic bone disease, and/or low serum PTH levels [90].

Phosphate binding and lowering of serum phosphate can be achieved with calcium-based or non-calcium-based binders. A meta-analysis including 11 randomized trials (4622 patients) showed that patients assigned to non-calcium-based binders had a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders in patients with CKD [100].

#### *3.2.2.3 Dialysate calcium*

The exposure to high calcium concentrations may influence the development of low–turnover bone disease and CAC in HD patients. A randomized controlled study showed that lowering Ca exposure through dialysate (dialysate Ca concentration of 1.25 mmol/L vs. 1.75 mmol/L) attenuates progression of CAC and improves low bone turn-over in HD patients with baseline PTH levels ≤300 pg./ml [101].

#### *3.2.2.4 Secondary hyperparathyroidism and adynamic bone disease*

Both secondary hyperparathyroidism (SHPT) high-turnover renal osteodystrophy and adynamic bone disease have been associated with VC. In a group of 58 ESRD patients on HD, bone-histomorphometry characteristics were compared with the arterial calcification (AC) scores. High AC scores were associated with bone histomorphometry values, suggestive of low bone activity and adynamic bone disease. This indicates that therapeutic interventions associated with excessive decrease of parathyroid activity favors lower bone turnover and adynamic bone disease that, in combination with interventions that increase the Ca balance, could influence the development and progression of AC [102].

#### *3.2.2.5 Vitamin D and calcimimetic agents*

A major complication of SHPT is renal osteodystrophy, in association with alterations in calcium and phosphorus metabolism leading to CV calcification. Active vitamin D compounds and calcimimetic agents are used to treat SHPT in dialysis patients. Untreated vitamin D deficiency has been associated with increased VC, in part due to accelerated development of atherosclerosis [103, 104]. In these patients, vitamin D supplement may have a protective benefit against VC by decreasing endothelial injury, inactivating renin-angiotensin-aldosterone system, decreasing insulin resistance, lowering cholesterol, inhibiting foam cell and cholesterol efflux in macrophages, and modulating vascular regeneration [105]. Excessive administration of vitamin D has been also associated with increased VC, possibly related to hypercalcemia and an elevated calcium-phosphate product. Cinacalcet

*Vascular Calcification and Cardiovascular Risk in Chronic Kidney Disease: A Problem That Is… DOI: http://dx.doi.org/10.5772/intechopen.99886*

has the ability to simultaneously lower PTH, calcium, phosphorus, and CaxP in patients with SHPT [106]. In a study, Cinacalcet plus low-dose active vitamin D derivatives attenuated vascular and cardiac valve calcification [107].
