Bone Markers Predict Cardiovascular Events in Chronic Kidney Disease

Fahrleitner‐Pammer, Astrid; Herberth, Johann; Browning, Steven R.; Obermayer–Pietsch, Barbara; Wirnsberger, Gerhard; Holzer, Herwig; Dobnig, Harald; Malluche, Hartmut H.

doi:10.1359/jbmr.080610

Cited by 86 publications

(53 citation statements)

References 46 publications

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“…This association was independent of serum calcium, phosphorus, parathyroid hormone (PTH), fetuin A, and C-reactive protein. In another study of 135 stages I through V CKD patients with limited adjustment for gender, CKD stage, serum PTH, and tartrate-resistant acid phosphatase 5b, the highest tertile of alkaline phosphatase was associated with increased risk of cardiovascular events (10).…”

Section: Discussionmentioning

confidence: 97%

Serum Alkaline Phosphatase and Mortality in African Americans with Chronic Kidney Disease

Beddhu

Baird

et al. 2009

Clinical Journal of the American Society of Nephrology

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Background and objectives: Serum alkaline phosphatase has been associated with increased mortality in hemodialysis patients but its associations with mortality in chronic kidney disease (CKD) stages III and IV are unknown.Design, settings, participants & measurements: In 1094 participants in the African-American Study of Kidney Disease and Hypertension (AASK) database, the associations of serum alkaline phosphatase with mortality and cardiovascular events were examined in Cox models.Results: The mean (؎SD) age was 54 ؎ 11 yr, and 61% were men. The median alkaline phosphatase was 80 IU/L, and interquartile range was 66 to 97 IU/L. The mean follow-up was 4.6 yr. There were 105 (9.6%) all-cause deaths and 149 (13.6%) cardiovascular events. Each doubling of serum alkaline phosphatase was significantly associated with increased hazard [hazard ratio (HR) 1.60, 95% confidence interval (CI) 1.08 ؊2.36] of all-cause mortality adjusted for demographics, drug and blood pressure groups, and comorbidity. With further adjustment for liver function tests as well as serum calcium and phosphorus, each doubling of serum alkaline phosphatase remained significantly associated with increased mortality (HR 1.55, 95% CI 1.03 to 2.33). Serum alkaline phosphatase was not significantly associated with increased risk of cardiovascular events.Conclusions: Independent of liver function tests and serum calcium and phosphorus, higher levels of serum alkaline phosphatase are associated with increased mortality in the CKD population. Further studies are warranted to identify the potential mechanisms for this association.

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Section: Discussionmentioning

confidence: 97%

Serum Alkaline Phosphatase and Mortality in African Americans with Chronic Kidney Disease

Beddhu

Baird

et al. 2009

Clinical Journal of the American Society of Nephrology

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“…Studies in renal osteopathy have produced inconclusive results with regard to the effect of renal function on serum TRACP 5b concentrations. While some studies found that TRACP 5b was not increased with renal dysfunction, 30,31 other studies showed haematologica | 2011; 96(8) that secondary hyperparathyroidism in chronic renal failure was associated with increased TRACP 5b 32 and that TRACP 5b concentration correlated inversely with glomerular filtration rate in pre-dialysis patients with chronic kidney disease. 33 The lack of a correlation between serum creatinine and TRACP 5b concentrations in this study may reflect the effect of body mass on creatinine.…”

Section: Beta (95% Ci) P Standardized Betamentioning

confidence: 99%

Predictors of osteoclast activity in patients with sickle cell disease

Nouraie¹,

Cheng²,

Niu³

et al. 2011

Haematologica

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BackgroundBone changes are common in sickle cell disease, but the pathogenesis is not fully understood. Tartrate-resistant acid phosphatase (TRACP) type 5b is produced by bone-resorbing osteoclasts. In other forms of hemolytic anemia, increased iron stores are associated with osteoporosis. We hypothesized that transfusional iron overload would be associated with increased osteoclast activity in patients with sickle cell disease. Design and MethodsWe examined tartrate-resistant acid phosphatase 5b concentrations in patients with sickle cell disease and normal controls of similar age and sex distribution at steady state. Serum tartrateresistant acid phosphatase 5b concentration was measured using an immunocapture enzyme assay and plasma concentrations of other cytokines were assayed using the Bio-Plex suspension array system. Tricuspid regurgitation velocity, an indirect measure of systolic pulmonary artery pressure, was determined by echocardiography. ResultsTartrate-resistant acid phosphatase 5b concentrations were higher in 58 adults with sickle cell disease than in 22 controls (medians of 4.4 versus 2.4 U/L, respectively; P=0.0001). Among the patients with sickle cell disease, tartrate-resistant acid phosphatase 5b independently correlated with blood urea nitrogen (standardized beta=0.40, P=0.003), interleukin-8 (standardized beta=0.30, P=0.020), and chemokine C-C motif ligand 5 (standardized beta=-0.28, P=0.031) concentrations, but not with serum ferritin concentration. Frequent blood transfusions (>10 units in life time) were not associated with higher tartrate-resistant acid phosphatase 5b levels in multivariate analysis. There were strong correlations among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity (r>0.35, P<0.001). ConclusionsPatients with sickle cell disease have increased osteoclast activity as reflected by serum tartrateresistant acid phosphatase 5b concentrations. Our results may support a potential role of inflammation rather than increased iron stores in stimulating osteoclast activity in sickle cell disease. The positive relationships among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity raise the possibility of a common pathway in the pulmonary and bone complications of sickle cell disease.Key words: sickle cell disease, osteoclast activity, bone turnover, inflammation, TRACP 5b, pulmonary complications.Citation: Nouraie M, Cheng K, Niu X, Moore-King E, Fadojutimi-Akinsi MF, Minniti CP, Sable C, Rana S, Dham N, Campbell A, Ensing G, Kato GJ, Gladwin MT, Castro OL, and Gordeuk VR. Predictors of osteoclast activity in sickle cell disease patients. Haematologica 2011;96(8):1092-1098. doi:10.3324/haematol.2011 This is an open-access paper. Predictors of osteoclast activity in patients with sickle cell disease

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“…(4) Evidence suggests that vascular disease is at least partially related to poor bone health. (5)(6)(7)(8) Importantly, deviation from the normal range of serum bone biomarkers predicts an increased risk of cardiovascular events, (9) and impaired bone remodeling is associated with increased vascular calcification. (10) In the general population, individuals with osteoporosis have increased atherosclerosis and coronary artery calcification (11)(12)(13)(14) and there is an inverse relationship between coronary artery calcification and bone mineral density (BMD) in both normal and CKD patients.…”

Section: Introductionmentioning

confidence: 99%

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Sabbagh

Graciolli

O’Brien

et al. 2012

Journal of Bone and Mineral Research

240

224

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Chronic kidney disease–mineral bone disorder (CKD‐MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft‐tissue calcification. Emerging evidence suggests that features of CKD‐MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild‐type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD‐MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild‐type mice. To capture the early molecular and cellular events in the progression of CKD‐MBD we examined cell‐specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor‐Ser33/37‐β‐catenin was observed both in mouse and human bones. Overall repression of Wnt/β‐catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF‐κB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late‐stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD‐MBD and suggest that repression of the Wnt/β‐catenin pathway is involved in the pathogenesis of renal osteodystrophy. © 2012 American Society for Bone and Mineral Research.

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Bone Markers Predict Cardiovascular Events in Chronic Kidney Disease

Cited by 86 publications

References 46 publications

Serum Alkaline Phosphatase and Mortality in African Americans with Chronic Kidney Disease

Serum Alkaline Phosphatase and Mortality in African Americans with Chronic Kidney Disease

Predictors of osteoclast activity in patients with sickle cell disease

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

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