Accelerated Vascular Calcification in Chronic Kidney Disease and Hypertension – Implications for New Concepts

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Accelerated Vascular Calcification in Chronic Kidney Disease and Hypertension – Implications for New Concepts

The risk of CV diseases in patients with chronic renal disease appears to be far greater than in the general population.³ Among patients treated by dialysis, the prevalence of coronary artery disease is approximately 40 % and the prevalence of left ventricular hypertrophy is approximately 75 %. CV mortality of dialysis patients has been estimated to be approximately 9 % per year.³ Even after stratification by age, gender, race and the presence or absence of diabetes, CV mortality in dialysis patients is 10–20 times higher than in the general population.³ These findings have prompted most hypertension guidelines to include the presence of CKD as a CV risk factor.⁷

Premature arterial calcification in CKD patients is one factor possibly increasing the CV risk. The natural history of coronary artery calcification has been studied in 22 young adults with ESRD by electron-beam computed tomography (EBCT).⁸ After a baseline assessment, computed tomography (CT) scanning was repeated at a mean of 22 ± 7 months later. Among 12 patients who had no evidence of coronary artery calcification on the initial scan, two had evidence of calcification on follow-up scanning. Among 10 of these 22 patients who had evidence of coronary artery calcification on the initial scan, nine had a higher calcification score on follow-up scanning; the values nearly doubled (from 125 ± 104 to 249 ± 216) over a mean period of 20 ± 3 months (p=0.02).

The mechanisms responsible for vascular calcifications in CKD patients remain uncertain, and the relation between arterial wall calcification and the atherosclerotic process is not fully understood. The factors involved in these complications are complex. Numerous metabolic and endocrine abnormalities involving calcium and phosphorus metabolism are found in CKD. Furthermore, CKD is believed to be a state of inflammation and oxidative stress. Most of these abnormalities occur early in the course of CKD and may contribute to the development and progression of vascular calcification and atherosclerosis. The mechanisms regulating the process of vascular calcification and the factors involved are subject to continued investigation. Both calcium and phosphorus directly stimulate vascular smooth muscle cell transformation into osteoblast-like cells and abnormal mineralization In vitro. The mechanisms whereby smooth muscle cells calcify appears to result from a complex interplay between factors that activate and inhibit tissue calcification.⁹ Matrix vesicles initiate mineral nucleation during skeletogenesis; similar vesicular structures are deposited at sites of pathologic vascular calcification. In vitro studies have shown that elevated levels of extracellular calcium and phosphorus can induce mineralization of vascular smooth muscle cells.¹⁰ In addition, numerous other factors have been shown, both In vitro and in vivo, to promote this process, in part through the production and activity of proteins like osteopontin, osteoprotegerin, osteocalcin, bone morphogenetic proteins and matrix Gla protein.⁸

Calcium deposits are found, however, in a large proportion of atherosclerotic lesions, providing the basis for the use of EBCT to screen for coronary artery disease.¹¹ Arterial layers are more frequently and more intensively calcified in uraemic patients than in non-uraemic patients, and participated to the progression of CKD.¹² Both the intima and media arterial layers are more frequently and more intensively calcified in uraemic patients than in non-uraemic individuals, and vascular and valvular calcification are both predictors of increased CV mortality and morbidity.¹³ In the atheromatous plaque, the most marked difference between uraemic and non-uraemic patients is not in its size but its composition, with a marked increase in calcium content in CKD patients.¹⁴

Vascular Calcification – Role of Vitamin D and Vitamin D Analogues

Calcitriol and various analogues are commonly used to suppress secondary hyperparathyroidism in CKD but may also exacerbate vascular calcification in experimental models; the mechanisms by which high doses of vitamin D or its derivatives induce vascular calcification include an increase in serum calcium and phosphate, the formation of fetuin-A mineral complexes in association with a decrease in free serum levels of fetuin-A.¹⁵ Some active vitamin D derivatives, when given in high amounts to animals with CKD, are not endowed with the same calcification-inducing capacity. For example, paricalcitol has been shown to be less pro-calcifying in uraemic rats than calcitriol or doxercalciferol. However, there are no prospective randomised controlled trials in CKD patients comparing the effect of native vitamin D or active vitamin D derivatives with placebo on vascular calcification. So far, the results of the PRIMO study (Paricalcitol capsules benefits in Renal failure Induced cardiac MOrbidity in subjects with chronic kidney disease Stage 3/4) that failed to show a beneficial effect of long-term paricalcitol administration over placebo on cardiac structure and function in CKD patients confirms the need for further intervention studies with firm outcomes.¹⁶