Reducing the Burden of Cardiovascular Calcification in Patients with Chronic Kidney Disease

Qunibi, Wajeh Y.

doi:10.1681/asn.2005060666

Cited by 49 publications

(32 citation statements)

References 59 publications

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“…Notably, patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease. 57 These patients often receive a high-calcium diet (to complex phosphate), vitamin D, and warfarin (to prevent thrombotic events). It was demonstrated, however, that each of these treatments is associated with an increased risk of arterial calcification.…”

Section: Discussionmentioning

confidence: 99%

Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats

Schurgers

Spronk

Soute

et al. 2006

Blood

230

204

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Arterial calcification (AC) is generally regarded as an independent risk factor for cardiovascular morbidity and mortality. Matrix Gla protein (MGP) is a potent inhibitor of AC, and its activity depends on vitamin K (VK). In rats, inactivation of MGP by treatment with the vitamin K antagonist warfarin leads to rapid calcification of the arteries. Here, we investigated whether preformed AC can be regressed by a VK-rich diet. Rats received a calcification-inducing diet containing both VK and warfarin (W&K). During a second 6-week period, animals were randomly assigned to receive either W&K (3.0 mg/g and 1.5 mg/g, subsequently), a diet containing a normal (5 g/g) or high (100 g/g) amount of VK (either K 1 or K 2 ). Increased aortic calcium concentration was observed in the group that continued to receive W&K and also in the group changed to the normal dose of VK and AC progressed. Both the VK-rich diets decreased the arterial calcium content by some 50%. In addition, arterial distensibility was restored by the VK-rich diet. Using MGP antibodies, local VK deficiency was demonstrated at sites of calcification. This is the first study in rats demonstrating that AC and the resulting decreased arterial distensibility are reversible by high-VK intake. IntroductionArterial calcification is an important independent risk factor for the development of atherosclerosis, myocardial infarction, stroke, and renal disease. 1,2 Patients with manifest arterial calcification have an unfavorable prognosis compared with patients with no or mild calcification. 3,4 Therefore, the prevention or reversal of arterial calcification may lead to improved patient outcomes.For a long time it has been thought that calcification was a passive process and the end stage of cardiovascular disease. During the past 10 years, however, it has become clear that several osteoregulatory proteins, both stimulatory and inhibitory, are involved in the calcification of vascular tissue. [5][6][7][8] One of the strongest in vivo inhibitors of arterial calcification is matrix Gla protein (MGP). MGP was first discovered in bone, 9 but it is mainly produced by vascular smooth muscle cells and chondrocytes. Its function became clear in MGP-deficient mice, 10 which died within 6 to 8 weeks after birth as a result of rupture of the large arteries. Histochemical evaluation demonstrated complete calcification of the elastic fibers in the arterial vessels and a phenotypic change of smooth muscle cells into chondrocytes. MGP acts by direct inhibition of calcium crystal formation and regulates bone morphogenetic protein-2, a growth factor responsible for osteogenic differentiation. [11][12][13] Murshed et al 14 demonstrated that restoration of MGP exclusively in the vascular smooth muscle cells of the MGP-null mice completely rescued the vascular calcification phenotype. For this effect the MGP needed to be ␥-carboxylated because mutating the Gla residues into aspartic acid residues led to the synthesis of nonfunctional MGP and to the death of all animals.Vitamin K is an e...

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Section: Discussionmentioning

confidence: 99%

Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats

Schurgers

Spronk

Soute

et al. 2006

Blood

230

204

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“…[93][94][95] A recent study showed that 40% of patients with CKD and a mean GFR 33 mL/min exhibited coronary artery calcification compared with 13% in matched control subjects with no renal impairment. 96 Calcification can be found in atherosclerotic plaques and in the vascular media, smooth muscle cells, and elastic laminae of large elastic and medium muscular arteries as well as in cardiac valves.…”

Section: Vascular Calcification Inducers and Inhibitors Of Calcificamentioning

confidence: 99%

“…96 Calcification can be found in atherosclerotic plaques and in the vascular media, smooth muscle cells, and elastic laminae of large elastic and medium muscular arteries as well as in cardiac valves. [93][94][95] Subjects with renal failure who exhibit medial calcification are typically middle-aged and have been dialyzed for some time, although some individuals may already have calcified vessels before dialysis. 97 There is a specific dialysis-related type of vascular calcification called calciphylaxis, or calcific uremic arteriopathy, that is characterized by diffuse calcification of the media of small to medium arteries and arterioles with intimal proliferation and thrombosis that results in skin ulcers 98 and can lead to life-threatening skin necrosis or acral gangrene.…”

Section: Vascular Calcification Inducers and Inhibitors Of Calcificamentioning

confidence: 99%

Chronic Kidney Disease

2007

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Abstract-Accelerated cardiovascular disease is a frequent complication of renal disease. Chronic kidney disease promotes hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. Furthermore, diabetic nephropathy is the leading cause of renal failure in developed countries. Together, hypertension, dyslipidemia, and diabetes are major risk factors for the development of endothelial dysfunction and progression of atherosclerosis. Inflammatory mediators are often elevated and the renin-angiotensin system is frequently activated in chronic kidney disease, which likely contributes through enhanced production of reactive oxygen species to the accelerated atherosclerosis observed in chronic kidney disease. Promoters of calcification are increased and inhibitors of calcification are reduced, which favors metastatic vascular calcification, an important participant in vascular injury associated with end-stage renal disease. Accelerated atherosclerosis will then lead to increased prevalence of coronary artery disease, heart failure, stroke, and peripheral arterial disease. Consequently, subjects with chronic renal failure are exposed to increased morbidity and mortality as a result of cardiovascular events. Prevention and treatment of cardiovascular disease are major considerations in the management of individuals with chronic kidney disease. Key Words: atherosclerosis Ⅲ hypertension Ⅲ kidney Ⅲ vasculature I t is increasingly apparent that individuals with chronic kidney disease (CKD) are more likely to die of cardiovascular (CV) disease (CVD) than to develop kidney failure. 1,2 A large cohort study comprising Ͼ130 000 elderly subjects showed that increased incidence of CV events could be in part related to the fact that persons with renal insufficiency are less likely to receive appropriate cardioprotective treatments. 3 However, beyond the effects of lack of appropriate therapy, it is clear that accelerated CVD is prevalent in subjects with CKD. The first part of the present review will therefore focus on the epidemiological links between impairment of renal function and adverse CV events, between albuminuria and CV events, and between serum cystatin C and CVD. The second part of the present review will address the mechanisms that lead to the association of renal and CVD, which include hypertension, dyslipidemia, activation of the renin-angiotensin system, endothelial dysfunction and the role of asymmetric dimethyl arginine (ADMA), oxidative stress, and inflammation. Finally, mechanisms that are involved in vascular calcification often found in CKD and end-stage renal disease (ESRD) will be described. Additionally, ESRD is associated with several specific complications caused by the uremic state per se, which can contribute to the development and progression of CVD through volume overload with consequent hypertension, anemia, uremic pericarditis, and cardiomyopathy. However, these issues will not be addressed because the emphasis will be on CKD before ESRD is reached. In addition, t...

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“…Increased vascular calcification has also been invoked in cardiovascular disease among patients with renal disease. 7 PROactive was a double-blind, randomized, placebocontrolled study that investigated the effect of pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR␥) activating thiazolidinedione, on a combined end point of vascular events. 4 In PROactive, the decline in the primary end point (approximately 10%) was not statistically significant.…”

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confidence: 99%