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Vascular calcification in chronic kidney disease

Vascular calcification in chronic kidney disease
Authors:
Marc G Vervloet, MD, PhD
Mario Cozzolino, MD, PhD
Section Editors:
Jeffrey S Berns, MD
Nisha Bansal, MD
Deputy Editor:
Eric N Taylor, MD, MSc, FASN
Literature review current through: Jan 2024.
This topic last updated: Sep 20, 2023.

INTRODUCTION — Cardiovascular disease is the most common cause of death in patients with chronic kidney disease (CKD), including those with end-stage kidney disease on dialysis. The high cardiovascular risk may be due in part to excess vascular calcification.

The epidemiology, pathogenesis, risk factors, clinical significance, diagnosis, and management of CKD-related vascular calcification are discussed in this topic review.

EPIDEMIOLOGY — The reported prevalence of vascular calcification detected by computed tomography (CT) scan is greater than 80 percent among patients on dialysis [1-16] and 47 to 83 percent among patients with nondialysis chronic kidney disease whose estimated glomerular filtration rate is <60 mL/min/1.73 m2 [14,17-24]. A comprehensive systematic review of 30 studies over a period of 20 years demonstrated that the prevalence of calcification has been consistent over the last several decades [5,25].

PATHOGENESIS — All large and medium-sized muscular arteries and arterioles can calcify. By comparison, veins hardly ever calcify, unless injured or arterialized [26]. This difference is probably due to differences in mechanical forces and in histologic structure between arteries and veins.

Medial versus intimal calcification — Among patients with chronic kidney disease (CKD), there are two types of vascular calcification, with different pathogeneses [27,28]:

●Medial calcification – Calcification of the medial layer of arterial vessels is the major form of vascular calcification among patients with CKD. Medial calcification occurs as a result of both a phenotype switch of vascular smooth muscle cells to osteoblast–like cells and local inflammation [27,29-33]. The phenotype change is initiated by hyperphosphatemia, hypercalcemia, and, possibly, high concentrations of parathyroid hormone (PTH) as well as oxidative stress [34-36]. Hyperphosphatemia increases activity of the sodium-dependent phosphate cotransporters, PiT-1 and PiT-2 [37,38], promoting phosphate uptake by vascular smooth muscle cells and upregulating genes associated with matrix mineralization [27,29-33,37,39-41]. Hypercalcemia and hyperphosphatemia both increase the release of vascular smooth muscle cell-derived matrix vesicles, resulting in the deposition of hydroxyapatite [42-44]. The molecular mechanisms regulating these processes have not been completely defined but likely involve the inhibition of target genes by microRNAs [45]. Other studies have demonstrated that specific abnormalities on genomic, transcriptomic, proteomic, and metabolic levels may all be involved and hold promise for future characterization and specific interventions [46].

Systemic and local inflammation also appear to play a key role in vascular calcification, although for many of the metabolites identified in multi-omics studies, their specific roles have not been identified. (See 'Role of inflammation and oxidative stress' below.)

Vascular calcification is inhibited by multiple regulatory proteins, and dysregulation of this aspect also contributes to its development. (See 'Calciprotein particles and inhibitors' below.)

●Intimal calcification – Calcification of the intimal layer of arterial vessels is secondary to established atherosclerosis. The pathogenesis of atherosclerosis appears to be the same in patients with or without CKD. (See "Pathogenesis of atherosclerosis", section on 'Pathogenesis'.)

However, mechanisms that contribute to intimal calcification, such as shear stress, local inflammation, and the calcification of macrophage and vascular smooth muscle cell-derived microvesicles, are amplified in patients with CKD [42,47,48]. Many of the factors that cause medial calcification (hyperphosphatemia, hypercalcemia, and hyperparathyroidism) likely worsen intimal calcification of preformed atherosclerotic plaques. In addition, the arterial stiffness caused by medial calcification likely directly contributes to the shear stress, atherosclerosis, and calcification of the intima [49].

Role of inflammation and oxidative stress — Inflammation plays a crucial role in calcification [50,51]. Infiltrating macrophages release proinflammatory cytokines that drive the influx of lymphocytes and smooth muscle cells [52]. Cellular microvesicles released from macrophages or apoptotic macrophages form a nidus for calcification, and macrophage-derived inflammatory regulators, such as matrix metalloproteinases and cathepsin S, contribute to the disintegration of elastic fibers and matrix components in the vessel wall, all which may promote calcification. (See "Pathogenesis of atherosclerosis".)

Inflammation also drives oxidative stress, which contributes to vascular calcification [53]. In turn, many antioxidant treatments have been proposed to ameliorate calcification, mediated by the Kelch-like ECH-associated protein 1/NF-E2-related factor 2 (KEAP/NRF2) system, a highly evolutionary conserved defense system against oxidative stress [54].

It is not clear whether the osteogenic transformation of vascular smooth muscle cells and mineralization are causes or effects of local inflammation [27].

Calciprotein particles and inhibitors — Vascular calcification is inhibited by multiple regulatory proteins. Deficiency of these proteins, such as can be seen in the setting of CKD and end-stage kidney disease, can contribute to vascular calcification.

●Calciprotein particles – Calciprotein particles (CPPs) are circulating particles composed of calcium-phosphate crystals and chaperone-binding proteins [55]. These chaperone-binding proteins inhibit the crystallization of calcium-phosphate in blood at physiologic serum concentrations of calcium and phosphate [55-58]. Fetuin A is the major chaperone-binding protein found in CPPs, but albumin and other plasma proteins are also crucial components [59].

A decreased concentration of fetuin A allows the precipitation of calcium-phosphate. As an example, the sera of patients on hemodialysis with low fetuin A concentrations has been shown to have impaired capacity to inhibit calcium-phosphate precipitation in vitro [60]. Increased calcium-phosphate precipitation contributes to vascular calcification. Studies have shown an association between low serum fetuin A concentrations and increased vascular calcification in patients on dialysis [60-65].

CPPs also contain matrix Gla-protein (MGP) and gamma-carboxylated Gla-rich protein (GRP), which, like fetuin A, are circulating inhibitors of calcification [27,66]. MGP and GRP are dependent upon vitamin K to exert their activity [27,67,68]. The inhibition of this activation of GRP and MGP may contribute to vascular calcification in patients on warfarin [69-71].

When expression of these inhibitory proteins is reduced, high concentrations of phosphate and/or calcium can overwhelm the protective capacity against the formation of circulating hydroxyapatite crystals. This results in the conversion of amorphic primary CPPs into crystalline “secondary” CPPs that worsen local inflammation and initiate tissue crystallization, thereby contributing to vascular calcification and inflammation [56,59]. The formation rate from primary to secondary CPPs reflects an individual’s intrinsic defense against ectopic calcification [72]. A slower formation rate (as can be quantified by the T50 score) reflects better inherent protection against calcification. In studies of patients with nondialysis CKD [48], patients on hemodialysis [73], and kidney transplant recipients [74,75], a lower T50, indicating more rapid formation of secondary CPPs, was associated with mortality after adjusting for confounders. Another study of patients with nondialysis CKD found that the T50 score was associated with atherosclerotic events and all-cause mortality [76]. This association was lost after adjustment for estimated glomerular filtration rate (eGFR). Whether improving the T50 for a given eGFR also lowers the risk for cardiovascular events and mortality is unknown.

●Other inhibitors – Other factors that inhibit calcification include klotho, pyrophosphate, osteoprotegerin, magnesium, and iron [27,40,77-86]:

•Alpha-klotho is a membrane protein that is highly expressed in the kidney, where it can be cleaved and enters the systemic circulation; levels of klotho decrease with progressive CKD [87]. Klotho increases phosphate excretion and inhibits phosphate uptake by vascular smooth muscle [40].

•Pyrophosphate is produced by vascular smooth muscle cells and inhibits formation of hydroxyapatite. Pyrophosphate is reduced in patients with CKD, particularly those on dialysis [81], and the administration of pyrophosphate reduces ectopic calcification without apparent untoward effects on bone in laboratory studies [77].

•Osteoprotegerin competes with the receptor activator of NF-kB ligand (RANKL) and its receptor, RANK, on osteoclast precursor cell membranes [82]. RANKL and osteoprotegerin promote and protect against vascular calcification, respectively [83]. However, the clinical effect of osteoprotegerin activity is not completely clear, and both low- and high-serum concentration of osteoprotegerin have been associated with vascular calcification [63,88,89].

•A number of experimental studies have suggested that the administration of magnesium prevents vascular calcification [78-80,84]. Potential mechanisms include the inhibition of calcium-phosphate crystal growth in the circulation, thereby decreasing calcium-phosphate deposition, and prevention of the phenotype change of vascular smooth muscle to osteoblasts [78]. Clinical studies that have examined the role of magnesium are described elsewhere in this topic. (See 'Other risk factors' below.)

•Iron (Fe3+) can retard calcification of vascular smooth muscle cells, at least in part by preventing apoptosis [85], and appears to also be protective at later stages of calcification if already established [86,90].

Other potentially regulatory factors include activin-A, several bone morphogenic proteins, osteopontin, zinc, and PTH-related protein [91-96].

RISK FACTORS — The following factors have been associated with medial and/or intimal vascular calcification and are generally specific to, or disproportionately represented among, patients with chronic kidney disease (CKD). Risk factors in the general population are discussed elsewhere, though are also present in the CKD population.

Since techniques used to identify calcification do not reliably distinguish between medial and intimal lesions, risk factors that are specific to either lesion have not been identified but likely overlap [97].

Increasing age and dialysis vintage — Increasing age and time on dialysis are associated with increased prevalence of vascular calcification [2,4,5]. In a comprehensive systematic review of 30 studies over a period of 20 years, age and dialysis vintage were the main factors associated with vascular calcification among patients with CKD [5].

In one study that included 364 skeletal radiographs in 152 patients with CKD, vascular calcification was observed in 30 and 50 percent of patients aged 15 to 30 and 40 to 50 years, respectively. In another study, vascular calcification was observed in 39 percent of patients starting dialysis and in 92 percent after a mean period of 16 years on dialysis [4].

Besides the prevalence, the severity of calcification also increases with age and dialysis vintage [4].

Hyperphosphatemia and hypercalcemia — Persistent hyperphosphatemia, particularly in the setting of intermittent or persistent hypercalcemia, drives the initiation and progression of vascular calcification [2,11,16,77,98]. In a study including 205 patients on hemodialysis, coronary artery calcification (CAC) was directly related to individual calcium and phosphate concentrations [11]. A 1 mg/dL higher calcium concentration had the same effect on calcification as an increase in dialysis vintage of more than five years; a 1 mg/dL higher phosphate concentration had the same effect as 2.5 more years on dialysis. (See 'Increasing age and dialysis vintage' above.)

Increased calcium-phosphate product is also associated with higher vascular calcification risk. In one study that included 39 young patients on dialysis (mean age 19 years), the serum calcium-phosphate product was higher among patients with CAC compared with dialysis patients without CAC (65 versus 56 mg2/dL2), while the serum concentrations of calcium alone and phosphate alone were not significantly different between the two groups [2].

The serum concentrations, particularly of calcium, do not necessarily reflect local concentrations, which, particularly at sites of inflammation like the arterial wall, can be much higher [99]. At sites of inflammation, calcification can occur even in the absence of hypercalcemia, hyperphosphatemia, or an elevated calcium-phosphate product. In addition, patients with CKD may be in positive calcium balance even if the serum calcium concentration is normal and there is no increase in the calcium-phosphate product. (See 'Oral calcium intake' below.)

Oral calcium intake — Increased oral calcium intake has been associated with higher risk of calcification [2]. In one study, the daily calcium intake was almost twice as high among individuals with vascular calcification compared with those without (6456 versus 3325 mg/day) [2].

This has important implications regarding the use of calcium-containing phosphate binders, which markedly increases total dietary calcium intake. Normal dietary calcium intake is on the order of 1000 mg per day. The prescription of 500 mg elemental calcium (1250 mg calcium carbonate) with meals leads to a substantial increase in calcium intake. In the study cited above [2], the near doubling of calcium intake was mainly due to differences in the use of calcium-containing phosphate binders.

Phosphate binders — A number of studies have specifically examined the increased risk conferred by calcium-containing phosphate binders in patients with CKD, as discussed below.

●Patients on dialysis – Among patients on dialysis, calcium-containing phosphate binders have been associated with increased progression of vascular calcification compared with the non-calcium-containing binder, sevelamer [2,3,100-105]. In the Treat-to-Goal and Renagel in New Dialysis (RIND) trials, which randomly assigned patients on hemodialysis to sevelamer or calcium-based phosphate binders, those on calcium-containing binders had more coronary artery or aortic vascular calcification at 12 to 24 months [3,101].

However, the dose of calcium-containing binders was high in these trials (approximately 4 g per day) and exceeded the maximum of what is presently recommended [106]. In addition, sevelamer may have reduced calcification by mechanisms unrelated to calcium intake. As an example, sevelamer has been shown to reduce serum low-density lipoprotein cholesterol (LDL-C) levels [3,107-110], and this lipid-lowering effect could confer the decrease in calcification risk. In support of this hypothesis, the Calcium Acetate Renagel Evaluation-2 (CARE-2) trial, in which lipid levels were controlled between groups, showed no difference in the progression of CAC with sevelamer and calcium acetate [111]. However, some have argued that the baseline risk for calcification in the CARE-2 trial was so high compared with that in the Treat-to-Goal and RIND studies that modifiability of the natural history of vascular calcification was lost [112].

Lanthanum has also been shown to decrease vascular calcification compared with calcium-containing phosphate binders in two trials [113,114]. In contrast with sevelamer, lanthanum is not known to have lipid-lowering effects. This suggests that the relative benefits of non-calcium-containing binders on vascular calcification are independent of lipid lowering.

●Patients not on dialysis – Calcium-containing binders appear to worsen the progression of vascular calcification among patients with CKD not on dialysis and who have baseline calcification, although they do not necessarily increase the prevalence of calcification [115].

•In the multicenter INDEPENDENT pilot trial, 212 consecutive patients with CKD and estimated glomerular filtration rates (eGFRs) between 30 and 60 mL/min/1.73 m2 were randomly assigned to receive sevelamer or calcium carbonate [102]. Among patients who had vascular calcification at baseline, regression in CAC occurred in more patients treated with sevelamer compared with calcium carbonate (24 versus 2, respectively). By 24 months, new vascular calcification developed in fewer patients treated with sevelamer compared with calcium carbonate (in 5 versus 45, respectively).

•In another trial of 148 patients with eGFR of 20 to 45 mL/min/1.73 m2 assigned to receive calcium acetate, lanthanum carbonate, sevelamer, or placebo, active therapy with any phosphate binder increased calcification of the coronary arteries and abdominal aorta compared with placebo [103]. However, this trial was underpowered to compare differences among the individual binders in the active-treatment groups. The progression of vascular calcification for the actively treated group may have been driven by the effect of calcium-containing binders [116].

In addition, in comparison with the INDEPENDENT trial, participants in this trial had a lower serum phosphate concentration at baseline (4.9 versus 4.2 mg/dL) [102,103]. This suggests that patients in this study were more able to maintain normal phosphate homeostasis and therefore were at lower risk of vascular calcification; as a result, patients in the INDEPENDENT trial may have been more likely to benefit from the intervention.

Role of positive calcium balance — The increased risk of excess calcium intake for progressive vascular calcification may be conferred by inducing a positive calcium balance, which is not always reflected by the serum calcium concentration. This was demonstrated in a randomized, placebo-controlled crossover trial that examined the effect of oral calcium carbonate administration on calcium and phosphate balance in eight patients with CKD and a mean eGFR of 15 to 59 mL/min/1.73 m2 [117]. Subjects received a controlled diet with either a calcium carbonate supplement (1500 mg/day calcium) or placebo during two three-week balance periods. Fasting blood and urine were collected at baseline and at the end of each week. All feces and urine were collected during weeks 2 and 3 of each balance period.

An oral and intravenous calcium isotope (45CaCl2) was administered to determine calcium kinetics. Patients were in neutral calcium and phosphorus balance while on the placebo. Calcium carbonate supplementation caused a positive calcium balance and had no effect on phosphorus balance. In addition, compared with placebo, calcium carbonate supplementation produced a small reduction in urine phosphorus excretion.

Calcium kinetics demonstrated positive net bone balance. However, the amount of calcium that was deposited in bone was less than the overall positive calcium balance, suggesting that some degree of soft-tissue deposition occurred. Fasting blood and urine biochemistries of calcium and phosphate homeostasis were unaffected by calcium carbonate, suggesting that it is futile to rely solely on blood concentrations to determine mineral excess or accumulation.

The interpretation of these data may be limited by the short-term nature of the study. It is possible that patients were not in steady state after only one week of calcium administration. If so, the short-term positive calcium balance that was observed may have been an appropriate response to correct years of bone calcium depletion and thus may flatten over time [118]. In studies of longer duration in predialysis CKD, 24-hour phosphate excretion substantially declined when calcium-containing binders were used [103].

Secondary hyperparathyroidism and adynamic bone disease — Both secondary hyperparathyroidism (ie, high-turnover renal osteodystrophy) and adynamic bone disease (low-turnover renal osteodystrophy) have been associated with vascular calcification [4,98,119-121].

●Hyperparathyroidism – In a study including 38 patients on hemodialysis, with 10 to 25 years of follow-up with annual skeletal series, vascular calcification was associated with hyperparathyroidism, with reduced progression after parathyroidectomy [4]. Similarly, in another study, serum parathyroid hormone (PTH) was higher among 52 patients with vascular calcification compared with 338 patients on hemodialysis who did not have vascular calcification (189 versus 145 pg/mL, respectively) [98]. A third study of patients on hemodialysis who underwent parathyroidectomy for severe secondary hyperparathyroidism found a reduction of calcification of the abdominal aorta after one year [122].

●Adynamic bone disease – Adynamic bone disease predisposes patients to vascular calcification [119-121]. In one study in patients on hemodialysis, an association was found between low bone turnover and vascular calcification [120]. Similarly, in a study of patients with nondialysis CKD, increased CAC was independently associated with lower bone formation [121].

In another study of patients on dialysis, there was a significant interaction between the dose of calcium-based phosphate binders and bone activity such that calcium load had a significantly greater impact on aortic calcification in patients with adynamic bone disease when compared with those with active bone disease [123]. It has been suggested that a lower capacity of bone to absorb calcium, due to low turnover, promotes its ectopic deposition. (See "Adynamic bone disease associated with chronic kidney disease".)

Vitamin D deficiency and excess — Both vitamin D deficiency and excess have been associated with increased vascular calcification.

●Vitamin D deficiency – Untreated vitamin D deficiency has been associated with increased vascular calcification [124,125]. In one analysis including individuals with and without CKD, lower serum vitamin D levels were associated with increased risk of developing CAC after adjusting for age, sex, race or ethnicity, site, season, body mass index, kidney function, and smoking history [124]. A suggested mechanism is that vitamin D deficiency decreases PTH-related peptide or bone morphogenic proteins, and this decrease enhances the transformation of vascular smooth muscle cells into osteoclasts [126]. (See 'Calciprotein particles and inhibitors' above.)

Among patients with vitamin D deficiency, vitamin D supplements may have protective effects against vascular calcification on the endothelium by inactivating renin-angiotensin-aldosterone system, decreasing insulin resistance, lowering cholesterol, inhibiting foam cell and cholesterol efflux in macrophages, and modulating vascular regeneration [127]. However, correction of vitamin D deficiency has not been shown to prevent vascular calcification.

●Vitamin D excess – Excessive administration of vitamin D has been associated with increased vascular calcification [4,128-131], possibly related to hypercalcemia and an elevated calcium-phosphate product, both of which are risk factors for vascular calcification (see 'Hyperphosphatemia and hypercalcemia' above). Excessive vitamin D administration may also cause adynamic bone disease, which is thought to be a risk factor for vascular calcification. (See 'Secondary hyperparathyroidism and adynamic bone disease' above.)

Vitamin K antagonists and deficiency — The role of vitamin K in the pathogenesis of vascular calcification is unclear. A number of studies of patients without CKD have suggested an association between warfarin (and/or other vitamin K antagonists) and increased cardiovascular calcification [132-140]. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Vascular calcification'.)

Warfarin and other vitamin K antagonists prevent the activation of vitamin K-dependent proteins such as matrix Gla protein (MGP) and gamma-carboxylated Gla-rich protein, which inhibit vascular calcification only in their active form [70,71]. (See 'Calciprotein particles and inhibitors' above.)

Higher concentrations of under-carboxylated MGP (ucMGP), which is a sensitive marker of vitamin K deficiency, are associated with increased calcification, independent from use of vitamin K antagonists [132,141,142]. ucMGP concentration is also predictive for the risk for calciphylaxis, an extreme form of severe arterial calcification of smaller cutaneous arteries leading to necrotic cutaneous lesions [143]. Use of warfarin and vitamin K deficiency are both important risk factors for calciphylaxis [144]. (See "Calciphylaxis (calcific uremic arteriolopathy)".)

The effects of vitamin K status on the progression of vascular calcification were evaluated in the Valkyrie trial, which randomly assigned 132 patients on hemodialysis with atrial fibrillation to a vitamin K antagonist, rivaroxaban, or rivaroxaban plus high-dose vitamin K2 for 18 months [145]. At baseline, plasma dephosphorylated ucMGP (dp-ucMGP) levels were elevated in all groups. Treatment with a vitamin K antagonist further increased dp-ucMGP levels, while treatment with rivaroxaban decreased dp-ucMGP levels but not back to normal; the decline in dp-ucMGP with rivaroxaban was more substantial among those also receiving vitamin K2. However, there were no significant changes in vascular calcification of the coronary artery or thoracic aorta among the treatment groups. In a subsequent trial in which 178 patients on hemodialysis were randomized to receive vitamin K2 plus standard care or standard care alone for 18 months, treatment with vitamin K2 decreased dp-ucMGP levels but had no appreciable effect on vascular calcification scores [146]. Because participants in this trial had high coronary artery calcification scores at baseline, these null results may not be generalizable to patients who have less severe vascular calcification.

Other risk factors

●Dialysate calcium – High dialysate calcium is associated with increased vascular calcification [147-149]. In a randomized trial including 425 hemodialysis patients, using a dialysate calcium of 1.25 mmol/L (2.5 mEq/L) slowed the rate of progression of CAC at 24 months compared with dialysate calcium of 1.75 mmol/L (3.5 mEq/L) [148].

●Hypomagnesemia – Hypomagnesemia has been associated with increased vascular calcification [27,98,150]. In one study that included 52 patients on hemodialysis with vascular calcification and 338 without, the serum magnesium was independently associated with vascular calcification after adjusting for age, sex, hemodialysis vintage, calcium, phosphate, and PTH concentration (odds ratio 0.28, 95% CI 0.09-0.92 per 1 mg/dL increase in serum magnesium) [98]. Similarly, in a study of 80 patients on peritoneal dialysis, a higher serum magnesium was associated with decreased aortic calcification after adjusting for age, serum phosphate, PTH, LDL-C, smoking history, and diabetes [150].

The effect of magnesium supplementation on vascular calcification in patients with CKD is uncertain. In an open-label trial that randomly assigned 123 patients with nondialysis CKD to magnesium oxide or placebo, the median change in CAC score at the time of interim analysis was smaller for patients receiving magnesium oxide (11 versus 40 percent), which led to early termination of the trial [151]. However, in a subsequent double-blinded, randomized, placebo-controlled trial that included 148 patients with nondialysis CKD, magnesium hydroxide had no effect on the progression of CAC [152]. Another trial of patients on hemodialysis found that increasing the dialysate magnesium prolonged the T50 score, decreasing the calcification propensity [153].

●Diabetes – Among patients without CKD, many studies have shown that diabetes is a risk factor for vascular calcification. This is also true among patients with both diabetes and CKD. In the Dallas Heart Study, among patients with eGFR <60 mL/min/1.73 m2 who were not on dialysis, diabetes increased the risk of vascular calcification from 3.5 to 55.7 percent [19]. However, the control group had a surprisingly low risk of vascular calcification in this study, which limits confidence in the observation.

●Dyslipidemia – Dyslipidemia increases the risk of vascular calcification in patients who do not have CKD.

Among patients with CKD or end-stage kidney disease, the lipid profile (primarily low high-density lipoprotein cholesterol [HDL-C], elevated triglycerides, elevated LDL, and elevated total cholesterol) was predictive of vascular calcification in multiple studies included in a systematic review [5]. As noted above, beneficial effects of sevelamer on vascular calcification may be related, at least in part, to its lipid-lowering effects. (See 'Phosphate binders' above.)

The mechanism is via induction of inflammation and endothelial/vascular smooth muscle cell damage by oxidized lipids. In addition, HDL regulates the osteoblastic differentiation of vascular cells, with lower HDL levels associated with increased adverse effects of oxidized LDL [7,154,155].

CLINICAL SIGNIFICANCE — The clinical significance of vascular calcification depends upon the site, histologic location (ie, medial or intimal), and type (ie, microcalcification or confluent large, calcified areas).

Coronary artery calcification — In the general population, coronary artery calcification (CAC) increases cardiovascular risk and adds independent prognostic information to that provided by the Framingham risk score. (See "Overview of possible risk factors for cardiovascular disease", section on 'Arterial calcification'.)

Among patients with chronic kidney disease (CKD), although vascular calcification is associated with increased cardiovascular risk and mortality, its additional predictive value to other cardiovascular risk factors is not clear [24,156-160]. In a prospective study including 104 patients on hemodialysis, mortality was higher among patients with a CAC score above the median compared with those below the median (98 versus 34 per 1000 patient-years, respectively). However, in analyses adjusted for other known cardiovascular risk factors, the increased mortality associated with having a CAC score above the median was not statistically significant (relative risk 2.7, 95% CI 0.87-8.3).

Assessing the prognostic value of calcification is more complex among patients with CKD than in the general population because there are two histologic subtypes with different pathogeneses and different clinical consequences [27] (see 'Medial versus intimal calcification' above). It is not known whether intimal and medial calcification both contribute to increased mortality, because it has been difficult to differentiate these lesions using standard radiographic techniques. (See 'Detection' below.)

In addition, within the subtype of intimal lesions, calcifications have various patterns of formation, which may have different clinical consequences [27]. Hydroxyapatite crystals may form as either large confluents or as microcalcifications. Large confluents support the fibrous cap of an atheromatous lesion and stabilize the lesion in CAC, thereby reducing the risk of plaque rupture [161]. Thus, a higher density of calcification that forms as a large confluent may be protective against thrombotic or occlusive cardiovascular events [162].

By contrast, microcalcifications of coronary arteries may increase vulnerability of the atheromatous plaque to mechanical stress imposed by blood pressure [27]. It is difficult to determine the clinical significance of microcalcifications with certainty because they are very difficult to detect using standard imaging techniques. (See 'Pathogenesis' above and 'Detection' below.)

Large-vessel calcification — Calcification of large conduit arteries like the aorta increases arterial stiffness [163]. Arterial stiffness or lack of distensibility causes hypertension and increased pulse pressure, which are risk factors for left ventricular dysfunction and heart failure among patients with CKD [163-165].

Type of calcification — There are no clinical studies that have conclusively identified differences in clinical implication of intimal versus medial lesions among patients with CKD. However, based on the pathogenic data described above, the major clinical effect of intimal calcification is in the formation and progression of atherosclerotic lesions resulting in coronary artery disease, cerebrovascular disease, and peripheral vascular disease. In one study of patients on hemodialysis, those with intimal calcification (with or without medial calcification) had the worst outcome [156]. However, medial calcification, in the absence of carotid atherosclerosis, and after adjustment for risk factors for atherosclerosis, also had major impact on clinical outcome [156]. (See 'Medial versus intimal calcification' above and "Pathogenesis of atherosclerosis" and "Overview of lower extremity peripheral artery disease", section on 'Anatomy and pathophysiology' and "Intracranial large artery atherosclerosis: Treatment and prognosis".)

Medial calcification decreases vascular distensibility leading to increased vessel stiffness and an increased pulse pressure [164]. This contributes to the risk of left ventricular hypertrophy, heart failure, myocardial infarction, and possibly stroke. As noted above, medial calcification also worsens the progression of intimal lesions.

Definite proof of clinical benefit to halt or regress either type of calcification is lacking. (See 'Medial versus intimal calcification' above.)

DETECTION — Vascular calcification is most often detected incidentally on imaging obtained for other purposes. We generally do not screen patients with chronic kidney disease for vascular calcification since there are no data to suggest that early detection benefits patients. Moreover, there is no evidence that interventions that slow progression of vascular calcification reduce the risk for clinically relevant outcomes.

A number of noninvasive methods have been developed for the detection and quantification of vascular calcification, mostly in the context of observational studies. The simplest technique is plain radiography, which demonstrates pipe-stem calcification of the tunica media and more irregular, patchy calcifications of the internal elastic lamina. Although plain radiography may differentiate to some degree between intimal and medial calcification, it is an insensitive method and does not quantify the severity of vascular calcification [156].

Computed tomography (CT) scan detects and quantifies vascular calcification but does not differentiate between intimal and medial calcium deposition. Coronary artery calcification (CAC) has been widely studied using this method. (See "Coronary artery calcium scoring (CAC): Overview and clinical utilization".)

Other techniques including vascular ultrasound, intravascular ultrasound, and optical coherence tomography have also been used to assess vascular calcification [27].

There may be a diagnostic role for mammograms, which have high spatial resolution and may be able to identify exclusively medial calcification [166].

Several scores, based on plain radiographic imaging or CT scans, are used in clinical studies:

●Agatston score – The Agatston score quantifies CAC detected by an unenhanced low-dose cardiac CT scan. The Agatston score allows for early risk stratification for a major adverse cardiac event. This is discussed in more detail elsewhere. (See "Coronary artery calcium scoring (CAC): Overview and clinical utilization".)

●Adragão score – The Adragão score quantifies calcification of the iliac, femoral, radial, and digital arteries observed on plain radiographs of the hands and pelvis. The final value ranges between 0 and 8 points (0 to 4 in the pelvis and 0 to 4 in the hands). In one study, a vascular calcification score ≥3 had an almost fourfold higher risk of cardiovascular mortality [167].

●Kauppila score – The Kauppila score quantifies the severity of lumbar aortic calcifications observed on a lateral abdominal radiograph that includes from the T-10 vertebra to the first two sacral vertebra [168]. A score of 1 to 3 is assigned based on extent of calcification (ie, one-third, two-thirds, or more than two-thirds of the vertebra length involved). Both the anterior and posterior part of the aorta are analyzed, resulting in a final score between 0 and 24 points.

PREVENTION AND TREATMENT

General measures — There is no specific therapy to prevent progression or to facilitate regression of vascular calcification in patients with chronic kidney disease (CKD). In addition, it remains uncertain if modifying the natural history of vascular calcification translates into improved patient outcomes.

The optimal management of vascular calcification in patients with CKD remains unclear. In general, preventive measures focus on addressing factors involved in pathogenesis of vascular calcification, such as treatment of persistent hyperphosphatemia, treatment of secondary hyperparathyroidism, regulating oral calcium intake, treatment of hypomagnesemia, and appropriate use of anticoagulation when indicated (see 'Risk factors' above). In addition, cardiovascular risk factors should also be managed as appropriate. These issues are discussed in greater detail in separate topic reviews:

●Treatment of hyperphosphatemia (see "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Treatment approach')

●Treatment of secondary hyperparathyroidism (see "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult patients on dialysis")

●Treatment of hypomagnesemia (see "Hypomagnesemia: Evaluation and treatment")

●Anticoagulation among patients with CKD (see "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Chronic kidney disease' and "Venous thromboembolism: Initiation of anticoagulation", section on 'Renal failure')

●Primary prevention of cardiovascular disease (see "Overview of primary prevention of cardiovascular disease" and "Overview of hypertension in acute and chronic kidney disease", section on 'Treatment of hypertension in chronic kidney disease' and "Lipid management in patients with nondialysis chronic kidney disease")

Investigational approaches — A number of investigational approaches have been evaluated for the ability to prevent progression of vascular calcification in patients on dialysis.

●Myo-inositol hexaphosphate – Myo-inositol hexaphosphate (SNF472) is an intravenous small molecule inhibitor of hydroxyapatite crystal growth. In a phase 2b trial that randomly assigned 274 patients on hemodialysis to treatment with SNF472 (300 or 600 mg) or placebo three times weekly during hemodialysis, patients receiving SNF472 had slower progression of coronary artery and aortic valve calcification, but not thoracic aorta calcification, at 52 weeks compared with those receiving placebo [169].

●Sodium thiosulfate – Sodium thiosulfate (STS) has been used to treat calciphylaxis among patients on hemodialysis. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Trial of sodium thiosulfate'.)

In a trial that randomly assigned 60 patients on hemodialysis with an abdominal aorta Agatston score ≥100 to receive STS or sodium chloride at the end of each hemodialysis session over six months, there was no difference in progression of calcification of the aorta between the groups [170]. However, patients receiving STS had slower progression of calcification of the iliac arteries, reduced pulse wave velocity (indicating less arterial stiffness), and a lower incidence of aortic valve calcification.

●Sotatercept – Sotatercept is an activin receptor type IIA-immunoglobulin G1 fusion protein trap that blocks activin-A activity at several sites including the vasculature. In a small randomized trial of 43 patients on dialysis, treatment with subcutaneous sotatercept, compared with placebo, showed a dose-dependent trend toward slowing progression of abdominal aortic vascular calcification [171].

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Vascular calcification is common among individuals with chronic kidney disease (CKD), particularly those on dialysis. Vascular calcification may contribute to cardiovascular disease and increased mortality among such patients, although this has not been proven. (See 'Epidemiology' above and 'Clinical significance' above.)

●Risk factors – Major risk factors for vascular calcification include increasing age and dialysis vintage; hyperphosphatemia, particularly in the setting of intermittent or persistent hypercalcemia; excessive oral calcium intake, including calcium-containing phosphate binders; and secondary hyperparathyroidism. Other important risk factors include vitamin D deficiency, use of vitamin K antagonists, hypomagnesemia, and dialysate calcium. (See 'Risk factors' above.)

●Detection – Vascular calcification is detected incidentally on imaging obtained for other purposes. We do not screen for vascular calcification among patients with CKD since there are no data to suggest that early detection benefits patients. (See 'Detection' above.)

●Management – There is no specific therapy to prevent progression or to facilitate regression of vascular calcification in patients with CKD. In addition, it remains uncertain if modifying the natural history of vascular calcification translates into improved patient outcomes. In general, preventive measures focus on addressing factors involved in pathogenesis of vascular calcification, such as treatment of persistent hyperphosphatemia, treatment of secondary hyperparathyroidism, regulating oral calcium intake, treatment of hypomagnesemia, and appropriate use of anticoagulation when indicated. In addition, cardiovascular risk factors should also be managed as appropriate. (See 'General measures' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Behdad Afzali MRCP, PhD, PGDip, FHEA, MAcadMEd, and David JA Goldsmith, MA, FRCP, who contributed to earlier versions of this topic review.

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  142. Parker BD, Schurgers LJ, Vermeer C, et al. The association of uncarboxylated matrix Gla protein with mitral annular calcification differs by diabetes status: The Heart and Soul study. Atherosclerosis 2010; 210:320.
  143. Nigwekar SU, Bloch DB, Nazarian RM, et al. Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis. J Am Soc Nephrol 2017; 28:1717.
  144. Nigwekar SU, Thadhani R, Brandenburg VM. Calciphylaxis. N Engl J Med 2018; 378:1704.
  145. De Vriese AS, Caluwé R, Pyfferoen L, et al. Multicenter Randomized Controlled Trial of Vitamin K Antagonist Replacement by Rivaroxaban with or without Vitamin K2 in Hemodialysis Patients with Atrial Fibrillation: the Valkyrie Study. J Am Soc Nephrol 2020; 31:186.
  146. Haroon S, Davenport A, Ling LH, et al. Randomized Controlled Clinical Trial of the Effect of Treatment with Vitamin K2 on Vascular Calcification in Hemodialysis Patients (Trevasc-HDK). Kidney Int Rep 2023; 8:1741.
  147. Cozzolino M, Carugo S. Low Dialysate Calcium: Between Low Arterial Calcification and Improved Low Bone Turnover. Blood Purif 2016; 42:1.
  148. Lu JR, Yi Y, Xiong ZX, et al. The Study of Low Calcium Dialysate on Elderly Hemodialysis Patients with Secondary Hypoparathyroidism. Blood Purif 2016; 42:3.
  149. Ok E, Asci G, Bayraktaroglu S, et al. Reduction of Dialysate Calcium Level Reduces Progression of Coronary Artery Calcification and Improves Low Bone Turnover in Patients on Hemodialysis. J Am Soc Nephrol 2016; 27:2475.
  150. Molnar AO, Biyani M, Hammond I, et al. Lower serum magnesium is associated with vascular calcification in peritoneal dialysis patients: a cross sectional study. BMC Nephrol 2017; 18:129.
  151. Sakaguchi Y, Hamano T, Obi Y, et al. A Randomized Trial of Magnesium Oxide and Oral Carbon Adsorbent for Coronary Artery Calcification in Predialysis CKD. J Am Soc Nephrol 2019; 30:1073.
  152. Bressendorff I, Hansen D, Schou M, et al. The Effect of Magnesium Supplementation on Vascular Calcification in CKD: A Randomized Clinical Trial (MAGiCAL-CKD). J Am Soc Nephrol 2023; 34:886.
  153. Bressendorff I, Hansen D, Schou M, et al. The Effect of Increasing Dialysate Magnesium on Serum Calcification Propensity in Subjects with End Stage Kidney Disease: A Randomized, Controlled Clinical Trial. Clin J Am Soc Nephrol 2018; 13:1373.
  154. Achenbach S, Ropers D, Pohle K, et al. Influence of lipid-lowering therapy on the progression of coronary artery calcification: a prospective evaluation. Circulation 2002; 106:1077.
  155. Parhami F, Basseri B, Hwang J, et al. High-density lipoprotein regulates calcification of vascular cells. Circ Res 2002; 91:570.
  156. London GM, Guérin AP, Marchais SJ, et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003; 18:1731.
  157. Sigrist MK, Taal MW, Bungay P, McIntyre CW. Progressive vascular calcification over 2 years is associated with arterial stiffening and increased mortality in patients with stages 4 and 5 chronic kidney disease. Clin J Am Soc Nephrol 2007; 2:1241.
  158. Goldsmith D, MacGinley R, Smith A, Covic A. How important and how treatable is vascular stiffness as a cardiovascular risk factor in renal failure? Nephrol Dial Transplant 2002; 17:965.
  159. London GM, Marchais SJ, Guerin AP, et al. Arterial structure and function in end-stage renal disease. Nephrol Dial Transplant 2002; 17:1713.
  160. Haydar AA, Hujairi NM, Covic AA, et al. Coronary artery calcification is related to coronary atherosclerosis in chronic renal disease patients: a study comparing EBCT-generated coronary artery calcium scores and coronary angiography. Nephrol Dial Transplant 2004; 19:2307.
  161. Ruiz JL, Weinbaum S, Aikawa E, Hutcheson JD. Zooming in on the genesis of atherosclerotic plaque microcalcifications. J Physiol 2016; 594:2915.
  162. Thomas IC, Forbang NI, Criqui MH. The evolving view of coronary artery calcium and cardiovascular disease risk. Clin Cardiol 2018; 41:144.
  163. Ohishi M, Tatara Y, Ito N, et al. The combination of chronic kidney disease and increased arterial stiffness is a predictor for stroke and cardiovascular disease in hypertensive patients. Hypertens Res 2011; 34:1209.
  164. Moody WE, Edwards NC, Chue CD, et al. Arterial disease in chronic kidney disease. Heart 2013; 99:365.
  165. Chen J, Mohler ER 3rd, Garimella PS, et al. Ankle Brachial Index and Subsequent Cardiovascular Disease Risk in Patients With Chronic Kidney Disease. J Am Heart Assoc 2016; 5.
  166. Duhn V, D'Orsi ET, Johnson S, et al. Breast arterial calcification: a marker of medial vascular calcification in chronic kidney disease. Clin J Am Soc Nephrol 2011; 6:377.
  167. Adragao T, Pires A, Lucas C, et al. A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients. Nephrol Dial Transplant 2004; 19:1480.
  168. Kauppila LI, Polak JF, Cupples LA, et al. New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study. Atherosclerosis 1997; 132:245.
  169. Raggi P, Bellasi A, Bushinsky D, et al. Slowing Progression of Cardiovascular Calcification With SNF472 in Patients on Hemodialysis: Results of a Randomized Phase 2b Study. Circulation 2020; 141:728.
  170. Djuric P, Dimkovic N, Schlieper G, et al. Sodium thiosulphate and progression of vascular calcification in end-stage renal disease patients: a double-blind, randomized, placebo-controlled study. Nephrol Dial Transplant 2020; 35:162.
  171. Coyne DW, Singh HN, Smith WT, et al. Sotatercept Safety and Effects on Hemoglobin, Bone, and Vascular Calcification. Kidney Int Rep 2019; 4:1585.
Topic 7222 Version 33.0

References

1 : Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients.

2 : Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.

3 : Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.

4 : Vascular calcification in long-term haemodialysis patients in a single unit: a retrospective analysis.

5 : Determinants of coronary vascular calcification in patients with chronic kidney disease and end-stage renal disease: a systematic review.

6 : A simple score predicts future cardiovascular events in an inception cohort of dialysis patients.

7 : Significant association between the progression of coronary artery calcification and dyslipidemia in patients on chronic hemodialysis.

8 : Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure.

9 : An association between coronary artery calcification score, lipid profile, and selected markers of chronic inflammation in ESRD patients treated with peritoneal dialysis.

10 : Coronary artery calcifications in children and young adults treated with renal replacement therapy.

11 : Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?

12 : Assessment of vascular calcification in ESRD patients using spiral CT.

13 : Coronary artery calcification measured with electron-beam computerized tomography correlates poorly with coronary artery angiography in dialysis patients.

14 : Coronary artery, aortic wall, and valvular calcification in nondialyzed individuals with type 2 diabetes and renal disease.

15 : Predictive Value of Measures of Vascular Calcification Burden and Progression for Risk of Death in Incident to Dialysis Patients.

16 : Progression of Vascular Calcification and Clinical Outcomes in Patients Receiving Maintenance Dialysis.

17 : Chronic kidney disease, plasma lipoproteins, and coronary artery calcium incidence: the Multi-Ethnic Study of Atherosclerosis.

18 : KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).

19 : Association between chronic kidney disease and coronary artery calcification: the Dallas Heart Study.

20 : Cardiovascular calcification in Hispanic Americans (HA) with chronic kidney disease (CKD) due to type 2 diabetes.

21 : Coronary artery calcification in patients with CRF not undergoing dialysis.

22 : Coronary artery calcification and mortality in diabetic patients with proteinuria.

23 : Association of mild to moderate kidney dysfunction and coronary calcification.

24 : Coronary Artery Calcification and Risk of Cardiovascular Disease and Death Among Patients With Chronic Kidney Disease.

25 : Prevalence of coronary artery calcification and its association with mortality, cardiovascular events in patients with chronic kidney disease: a systematic review and meta-analysis.

26 : [Calcified and ossified phlebosclerosis].

27 : Vascular calcification in chronic kidney disease: different bricks in the wall?

28 : Vascular calcification in end-stage renal disease.

29 : Association of serum alkaline phosphatase with coronary artery calcification in maintenance hemodialysis patients.

30 : Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells.

31 : Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins.

32 : Vascular calcification in uremic conditions: new insights into pathogenesis.

33 : The making of a bone in blood vessels: from the soft shell to the hard bone.

34 : Klotho-FGF23, Cardiovascular Disease, and Vascular Calcification: Black or White?

35 : Arterial calcification in chronic kidney disease: key roles for calcium and phosphate.

36 : Oxidative stress contributes to vascular calcification in patients with chronic kidney disease.

37 : Phosphate regulation of vascular smooth muscle cell calcification.

38 : Vascular calcification in chronic kidney disease: new developments in drug therapy.

39 : Fibroblast growth factor 23 inhibits osteoblastic gene expression and induces osteoprotegerin in vascular smooth muscle cells.

40 : Klotho deficiency causes vascular calcification in chronic kidney disease.

41 : The role of the anti-ageing protein Klotho in vascular physiology and pathophysiology.

42 : Calcium regulates key components of vascular smooth muscle cell-derived matrix vesicles to enhance mineralization.

43 : The influence of phosphate, calcium and magnesium on matrix Gla-protein and vascular calcification: a systematic review.

44 : Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD.

45 : Characterization and assessment of potential microRNAs involved in phosphate-induced aortic calcification.

46 : A multi-omics view of the complex mechanism of vascular calcification.

47 : Arterial and Cellular Inflammation in Patients with CKD.

48 : Serum calcification propensity predicts all-cause mortality in predialysis CKD.

49 : Between Rho(k) and a hard place: the relation between vessel wall stiffness, endothelial contractility, and cardiovascular disease.

50 : Pro: cardiovascular calcifications are clinically relevant.

51 : Con: vascular calcification is a surrogate marker, but not the cause of ongoing vascular disease, and it is not a treatment target in chronic kidney disease.

52 : Macrophage Phenotype and Function in Different Stages of Atherosclerosis.

53 : Influence of oxidative stress on vascular calcification in the setting of coexisting chronic kidney disease and diabetes mellitus.

54 : Activation of KEAP1/NRF2/P62 signaling alleviates high phosphate-induced calcification of vascular smooth muscle cells by suppressing reactive oxygen species production.

55 : Calciprotein particle (CPP): a true culprit of phosphorus woes?

56 : Calcification of vascular smooth muscle cells is induced by secondary calciprotein particles and enhanced by tumor necrosis factor-α.

57 : The inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin-mineral complex.

58 : Biochemical characterization of the serum fetuin-mineral complex.

59 : Cellular Clearance and Biological Activity of Calciprotein Particles Depend on Their Maturation State and Crystallinity.

60 : Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study.

61 : Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin.

62 : Deficiencies of calcium-regulatory proteins in dialysis patients: a novel concept of cardiovascular calcification in uremia.

63 : Coronary calcification in hemodialysis patients: the contribution of traditional and uremia-related risk factors.

64 : Cardiac calcifications: Fetuin-A and other risk factors in hemodialysis patients.

65 : Association of serum fetuin-A levels with mortality in dialysis patients.

66 : Chronic Kidney Disease Circulating Calciprotein Particles and Extracellular Vesicles Promote Vascular Calcification: A Role for GRP (Gla-Rich Protein).

67 : The circulating inactive form of matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification.

68 : The Role of Vitamin K Status in Cardiovascular Health: Evidence from Observational and Clinical Studies.

69 : Vascular Calcification, Vitamin K and Warfarin Therapy - Possible or Plausible Connection?

70 : Inflammatory, metabolic, and genetic mechanisms of vascular calcification.

71 : Oxidized low density lipoprotein increases RANKL level in human vascular cells. Involvement of oxidative stress.

72 : Nanoparticle-based test measures overall propensity for calcification in serum.

73 : Blood Calcification Propensity, Cardiovascular Events, and Survival in Patients Receiving Hemodialysis in the EVOLVE Trial.

74 : Calcification Propensity and Survival among Renal Transplant Recipients.

75 : Cardiovascular calcifications in kidney transplant recipients.

76 : Serum Calcification Propensity and Clinical Events in CKD.

77 : Treatment with pyrophosphate inhibits uremic vascular calcification.

78 : Magnesium Counteracts Vascular Calcification: Passive Interference or Active Modulation?

79 : Magnesium preventsβ-glycerophosphate-induced calcification in rat aortic vascular smooth muscle cells.

80 : Magnesium prevents vascular calcification in vitro by inhibition of hydroxyapatite crystal formation.

81 : Plasma pyrophosphate and vascular calcification in chronic kidney disease.

82 : Osteoprotegerin (OPG) is localized to the Weibel-Palade bodies of human vascular endothelial cells and is physically associated with von Willebrand factor.

83 : Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.

84 : Magnesium prevents vascular calcification in Klotho deficiency.

85 : Iron citrate reduces high phosphate-induced vascular calcification by inhibiting apoptosis.

86 : Therapeutic Effect of Iron Citrate in Blocking Calcium Deposition in High Pi-Calcified VSMC: Role of Autophagy and Apoptosis.

87 : The association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study.

88 : IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia--the good, the bad, and the ugly.

89 : Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD).

90 : Transforming the frail and elderly patient into an Iron Man: how to attenuate arterial calcification and improve cardiovascular outcomes in chronic kidney disease.

91 : 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide.

92 : Identifying early pathogenic events during vascular calcification in uremic rats.

93 : Osteopontin regulates macrophage activation and osteoclast formation in hypertensive patients with vascular calcification.

94 : Association between dietary zinc intake and abdominal aortic calcification in US adults.

95 : Zinc Inhibits Phosphate-Induced Vascular Calcification through TNFAIP3-Mediated Suppression of NF-κB.

96 : The role of activin: the other side of chronic kidney disease-mineral bone disorder?

97 : Vascular calcification: pathobiology of a multifaceted disease.

98 : Significant association between the presence of peripheral vascular calcification and lower serum magnesium in hemodialysis patients.

99 : Extracellular calcium elicits a chemokinetic response from monocytes in vitro and in vivo.

100 : Determinants of progressive vascular calcification in haemodialysis patients.

101 : Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.

102 : Mortality in kidney disease patients treated with phosphate binders: a randomized study.

103 : Effects of phosphate binders in moderate CKD.

104 : Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.

105 : Sevelamer Versus Calcium-Based Binders for Treatment of Hyperphosphatemia in CKD: A Meta-Analysis of Randomized Controlled Trials.

106 : Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters.

107 : Long-term effects of sevelamer hydrochloride on the calcium x phosphate product and lipid profile of haemodialysis patients.

108 : Meta-analysis of the effect of sevelamer on phosphorus, calcium, PTH, and serum lipids in dialysis patients.

109 : Sevelamer hydrochloride versus aluminum hydroxide: effect on serum phosphorus and lipids in CAPD patients.

110 : Potential antiatherogenic and anti-inflammatory properties of sevelamer in maintenance hemodialysis patients.

111 : A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: the Calcium Acetate Renagel Evaluation-2 (CARE-2) study.

112 : Calcium-containing phosphate binders in dialysis patients with cardiovascular calcifications: should we CARE-2 avoid them?

113 : Evaluation of aortic calcification with lanthanum carbonate vs. calcium-based phosphate binders in maintenance hemodialysis patients with type 2 diabetes mellitus: an open-label randomized controlled trial.

114 : Attenuation of aortic calcification with lanthanum carbonate versus calcium-based phosphate binders in haemodialysis: A pilot randomized controlled trial.

115 : Prevention and treatment of hyperphosphatemia in chronic kidney disease.

116 : Phosphate binders in CKD: bad news or good news?

117 : Oral calcium carbonate affects calcium but not phosphorus balance in stage 3-4 chronic kidney disease.

118 : A balanced view of calcium and phosphate homeostasis in chronic kidney disease.

119 : Adynamic bone disease: from bone to vessels in chronic kidney disease.

120 : Arterial calcifications and bone histomorphometry in end-stage renal disease.

121 : Coronary calcification is associated with lower bone formation rate in CKD patients not yet in dialysis treatment.

122 : Changes in serum FGF23 and Klotho levels and calcification scores of the abdominal aorta after parathyroidectomy for secondary hyperparathyroidism.

123 : Association of bone activity, calcium load, aortic stiffness, and calcifications in ESRD.

124 : 25-hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification.

125 : Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency.

126 : 1,25-(OH)2-vitamin D3 suppresses the bone-related Runx2/Cbfa1 gene promoter.

127 : Role of Vitamin D in Uremic Vascular Calcification.

128 : VITAMIN D-INDUCED AORTIC CALCIFICATION.

129 : Arterial calcification after vitamin-D therapy in hyperphosphatemic renal failure.

130 : Metastatic calcification of soft tissue on overdosage of vitamin D.

131 : Soft tissue calcification in pediatric patients with end-stage renal disease.

132 : The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report.

133 : Vitamin K deficiency in CKD patients: a modifiable risk factor for vascular calcification?

134 : Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): a rationale and study protocol.

135 : Increased vascular calcification in patients receiving warfarin.

136 : Increased Peripheral Arterial Calcification in Patients Receiving Warfarin.

137 : Slower Progress of Aortic Valve Calcification With Vitamin K Supplementation: Results From a Prospective Interventional Proof-of-Concept Study.

138 : Sevelamer Use, Vitamin K Levels, Vascular Calcifications, and Vertebral Fractures in Hemodialysis Patients: Results from the VIKI Study.

139 : Current Therapy in CKD Patients Can Affect Vitamin K Status.

140 : The Role of Vitamin K in Vascular Calcification.

141 : Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients.

142 : The association of uncarboxylated matrix Gla protein with mitral annular calcification differs by diabetes status: The Heart and Soul study.

143 : Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis.

144 : Calciphylaxis.

145 : Multicenter Randomized Controlled Trial of Vitamin K Antagonist Replacement by Rivaroxaban with or without Vitamin K2 in Hemodialysis Patients with Atrial Fibrillation: the Valkyrie Study.

146 : Randomized Controlled Clinical Trial of the Effect of Treatment with Vitamin K2 on Vascular Calcification in Hemodialysis Patients (Trevasc-HDK).

147 : Low Dialysate Calcium: Between Low Arterial Calcification and Improved Low Bone Turnover.

148 : The Study of Low Calcium Dialysate on Elderly Hemodialysis Patients with Secondary Hypoparathyroidism.

149 : Reduction of Dialysate Calcium Level Reduces Progression of Coronary Artery Calcification and Improves Low Bone Turnover in Patients on Hemodialysis.

150 : Lower serum magnesium is associated with vascular calcification in peritoneal dialysis patients: a cross sectional study.

151 : A Randomized Trial of Magnesium Oxide and Oral Carbon Adsorbent for Coronary Artery Calcification in Predialysis CKD.

152 : The Effect of Magnesium Supplementation on Vascular Calcification in CKD: A Randomized Clinical Trial (MAGiCAL-CKD).

153 : The Effect of Increasing Dialysate Magnesium on Serum Calcification Propensity in Subjects with End Stage Kidney Disease: A Randomized, Controlled Clinical Trial.

154 : Influence of lipid-lowering therapy on the progression of coronary artery calcification: a prospective evaluation.

155 : High-density lipoprotein regulates calcification of vascular cells.

156 : Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.

157 : Progressive vascular calcification over 2 years is associated with arterial stiffening and increased mortality in patients with stages 4 and 5 chronic kidney disease.

158 : How important and how treatable is vascular stiffness as a cardiovascular risk factor in renal failure?

159 : Arterial structure and function in end-stage renal disease.

160 : Coronary artery calcification is related to coronary atherosclerosis in chronic renal disease patients: a study comparing EBCT-generated coronary artery calcium scores and coronary angiography.

161 : Zooming in on the genesis of atherosclerotic plaque microcalcifications.

162 : The evolving view of coronary artery calcium and cardiovascular disease risk.

163 : The combination of chronic kidney disease and increased arterial stiffness is a predictor for stroke and cardiovascular disease in hypertensive patients.

164 : Arterial disease in chronic kidney disease.

165 : Ankle Brachial Index and Subsequent Cardiovascular Disease Risk in Patients With Chronic Kidney Disease.

166 : Breast arterial calcification: a marker of medial vascular calcification in chronic kidney disease.

167 : A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients.

168 : New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study.

169 : Slowing Progression of Cardiovascular Calcification With SNF472 in Patients on Hemodialysis: Results of a Randomized Phase 2b Study.

170 : Sodium thiosulphate and progression of vascular calcification in end-stage renal disease patients: a double-blind, randomized, placebo-controlled study.

171 : Sotatercept Safety and Effects on Hemoglobin, Bone, and Vascular Calcification.

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