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

Moe, Sharon M.; Reslerova, Martina; Ketteler, Markus; O’Neill, Kalisha D.; Duan, Danxia; Koczman, Jacob J.; Westenfeld, Ralf; Jahnen‐Dechent, Willi; Chen, Neal X.

doi:10.1111/j.1523-1755.2005.00333.x

Cited by 343 publications

(295 citation statements)

References 51 publications

(44 reference statements)

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“…The increased incidence of cardiovascular events in patients with CKD is related to both traditional and nontraditional cardiovascular risk factors 2. Nontraditional cardiovascular risk factors include uremia‐related factors, inflammation, and abnormal metabolism of calcium and phosphate 3, 4…”

Section: Introductionmentioning

confidence: 99%

Extracellular Fluid Excess Is Significantly Associated With Coronary Artery Calcification in Patients With Chronic Kidney Disease

Park

Jhee

Yun

et al. 2018

JAHA

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BackgroundExtracellular fluid (ECF) excess is an independent predictor of cardiovascular morbidity in patients undergoing dialysis. This study aimed to investigate the relationship between ECF status, which is affected by renal function, and coronary artery calcification (CAC), which is a marker of cardiovascular disease, in patients with chronic kidney disease (CKD).Methods and ResultsA total of 1741 patients at all stages of pre‐dialysis CKD from the prospective observational cohort of CMERC‐HI (Cardiovascular and Metabolic Disease Etiology Research Center‐High Risk) were analyzed for the association between ECF status and CAC. ECF status was defined as extracellular water‐to‐total body water ratio (ECW/TBW) measured using bioelectrical impedance analysis. ECF excess was defined as ECW/TBW ≥0.390 or ≥0.400 depending on its severity. To define CAC, Agatston coronary artery calcium scores were measured. A total coronary artery calcium score of ≥400 was defined as CAC. The CKD stages were defined according to estimated glomerular filtration rate calculated using the CKD Epidemiology Collaboration equation. ECW/TBW and the proportion of ECF excess increased with progressing CKD stages. Multivariable logistic regression analyses showed that ECW/TBW was independently associated with CAC (per 0.01 increase of ECW/TBW, odds ratio 1.168, 95% confidence interval, 1.079–1.264, P<0.001). The adjusted R 2 for predicting higher coronary artery calcium scores and CAC significantly improved after ECW/TBW was added to conventional factors. This association was further confirmed by net reclassification and integrated discriminant improvements, sensitivity analysis, and subgroup analysis.Conclusions ECF status is independently associated with a high risk of CAC in patients with CKD.Study Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02003781.

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Section: Introductionmentioning

confidence: 99%

Extracellular Fluid Excess Is Significantly Associated With Coronary Artery Calcification in Patients With Chronic Kidney Disease

Park

Jhee

Yun

et al. 2018

JAHA

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“…High osteoprotegerin values have also been linked to poor glycemic control58, 59 and severity of diabetic nephropathy 60, 61. In patients with chronic renal failure, levels of osteoprotegerin are higher compared with healthy controls,62 are inversely correlated with glomerular filtration rate,63 and correlate with time on maintenance hemodialysis in patients with end‐stage renal disease 64. Third, associations of osteoprotegerin may be attenuated because of the dominance of other factors more relevant to CVD risk in high‐risk patients, including highly prevalent traditional CVD risk factors as well as factors related to quality of clinical care, treatment response, or medication adherence 65.…”

Section: Discussionmentioning

confidence: 99%

Osteoprotegerin and Cardiovascular Events in High‐Risk Populations: Meta‐Analysis of 19 Prospective Studies Involving 27 450 Participants

Tschiderer

Klingenschmid

Nagrani

et al. 2018

JAHA

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BackgroundOsteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease (CVD) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear.Methods and ResultsThree independent reviewers systematically searched PubMed, EMBASE, and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high CVD risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow‐up of 4.2 years, 4066 CVD events were recorded. In a random‐effects meta‐analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12–1.50; P<0.001; I2=68.3%). There was evidence for presence of publication bias (P value from Egger's test=0.013). Correction for publication bias using the trim‐and‐fill method reduced the risk ratio to 1.21 (95% confidence interval, 1.03–1.42; P<0.001). The risk ratios did not vary significantly by population type, geographical region, statistical adjustment, sample or assay type, age, sex, or length of follow‐up.ConclusionsIn populations at high CVD risk, elevated circulating osteoprotegerin levels are associated with a higher risk for future CVD events. The magnitude of association appears weaker than in the general population.

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“…Further experimental studies have shown a direct association between increase of bone resorption, release of the calcium-phosphate-fetuin-MGP complex, and arterial calcifications [12]. Thus, the fetuin-A and MGP inhibition of extraosseous and, specifically, arterial calcifications is probably exerted locally in the soft tissues and can be somehow impaired in cases of high bone turnover and consequent increase of the mineral-containing complexes in the blood [2,12].…”

Section: Introductionmentioning

confidence: 99%

“…Vascular calcifications are of frequent occurrence in uremic subjects, and it is assumed that they greatly contribute to the increased cardiovascular mortality both in conservative and hemodialysis (HD) stages of uremia [1,2]. Several risk factors of vascular calcifications have been identified.…”

Section: Introductionmentioning

confidence: 99%

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Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

et al. 2009

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Matrix Gla protein (MGP) and fetuin-A are inhibitors of arterial calcifications. In blood of rats, calcium-phosphate-fetuin-MGP complexes, produced in bone, have been identified. Indeed, an association between bone resorption, release of such complexes, and arterial calcifications has been reported. We have investigated the synthesis and localization of fetuin-A and MGP in bone of hemodialysis patients and the possible contribution of bone cells in arterial calcifications. Bone biopsies from 11 hemodialysis patients were used for histology, in situ hybridization of fetuin-A and MGP messenger RNA (mRNA), immunohistochemistry of fetuin-A, and total, carboxylated, and non-carboxylated MGP proteins. Patients showed various types of renal osteodystrophy, or normal bone. MGP was synthesized and expressed (total and carboxylated) by osteoblasts, osteocytes, and most osteoclasts, while fetuin-A by osteoblasts and osteocytes. Fetuin-A and carboxylated MGP proteins were positive in the calcified matrix, while total MGP was negative. Osteoid seams were negative to fetuin-A, lightly positive to carboxylated MGP, and occasionally positive to total MGP. Undercarboxylated MGP was mostly undetectable. In adult humans, fetuin-A is produced also by osteoblasts, and not only by hepatocytes, as previously believed. MGP, essentially carboxylated, is synthesized by osteoblasts and most osteoclasts. Increased bone turnover can be an important contributor to arterial calcifications.

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

Abstract: These data demonstrate that fetuin-A, OPG, and MGP play an important role in the pathogenesis of uremic vascular calcification.

Cited by 343 publications

References 51 publications

Extracellular Fluid Excess Is Significantly Associated With Coronary Artery Calcification in Patients With Chronic Kidney Disease

Extracellular Fluid Excess Is Significantly Associated With Coronary Artery Calcification in Patients With Chronic Kidney Disease

Osteoprotegerin and Cardiovascular Events in High‐Risk Populations: Meta‐Analysis of 19 Prospective Studies Involving 27 450 Participants

Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

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