osteoprotegerin and Kidney-Failure--Chronic

Cardiovascular events make up the primary cause of death in hemodialysis patients, and the risk for cardiovascular mortality is significantly increased by vascular calcification, a condition observed frequently in this patient population. The mechanisms underlying the pathogenesis of vascular calcification are complex, and many factors facilitate or hinder the development of calcification. In this review, we first summarize the main factors contributing to the pathogenesis of vascular calcification in patients with end-stage renal disease. We then explore the role of calcification inhibitors in the calcification process, as well as their effect on vascular dysfunction and mortality in hemodialysis patients.

Topics: alpha-2-HS-Glycoprotein; Cardiotonic Agents; Cardiovascular Diseases; Cause of Death; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Osteopontin; Osteoprotegerin; Renal Dialysis; Risk Assessment; Survival Analysis; Treatment Outcome; Vascular Calcification

The mortality of end-stage renal disease (ESRD) patients, including those receiving long-term peritoneal dialysis (PD), has remained unacceptably high owing to the prevalence of cardiovascular disease. It is well recognized that both traditional Framingham risk factors and kidney disease-related risk factors may contribute to the high prevalence of cardiovascular disease in these patients. Of the different risk factors, chronic inflammation frequently is observed in long-term PD patients. The causes of inflammation are usually complex and multifactorial, involving both dialysis-related and dialysis-unrelated factors. Inflammation is strongly associated with cardiovascular disease and malnutrition, and has been shown consistently to be a powerful predictor of mortality and adverse cardiovascular outcomes in PD patients. In this article we review the prevalence and potential causes of chronic inflammation in PD patients. More importantly, we provide emerging evidence that shows the serious consequences of chronic systemic inflammation in PD patients and the important contribution of inflammation to adverse clinical outcomes.

Topics: C-Reactive Protein; Cachexia; Calcinosis; Cardiomegaly; Chronic Disease; Heart Failure; Humans; Inflammation; Insulin Resistance; Kidney Failure, Chronic; Osteoprotegerin; Peritoneal Dialysis; Prevalence

Disorders of bone and mineral metabolism affect almost all patients with advanced chronic kidney disease (CKD). High prevalence of decreased bone mineral density has been reported in this population; however, the role and diagnostic utility of bone density measurements are not well established. The incidence of bone fractures is high in patients with ESRD, but the association between fractures and bone density is not obvious. A recent meta-analysis suggested that decreased density at the radius might be associated with higher overall fracture risk. Changes in bone mineral density reflect several underlying pathological processes, such as vitamin D deficiency, estrogen deficiency and changes in bone turnover. The response of bone to these factors and processes is not uniform: it can vary in different compartments of the same bone or in different bones of the skeleton. Therefore, it is important to differentiate between the various types of bone. This may be possible by proper selection of the measurement site or using methods such as quantitative bone computed tomography. Previous studies used different methods and measured bone mineral density at diverse sites of the skeleton, which makes the comparison of their results very difficult. The association between changes in bone mineral metabolism and cardiovascular mortality is well known in ESRD patients. Studies also suggest that low bone density itself might be an indicator for high risk of cardiovascular events and poor overall outcome in this population. Some of the risk factors of low bone mineral density, such as vitamin D or estrogen deficiency, are potentially modifiable. Further studies are needed to elucidate if interventions modifying these risk factors will have an impact on clinical outcomes. In this review, we discuss the options for and problems of assessment of bone density and summarize the literature about factors associated with low bone density and its link to clinical outcomes in patients on maintenance dialysis.

Topics: Absorptiometry, Photon; Bone Density; Chronic Kidney Disease-Mineral and Bone Disorder; Estrogens; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fractures, Spontaneous; Humans; Kidney Failure, Chronic; Osteoprotegerin; Parathyroid Hormone; Peritoneal Dialysis; Renal Dialysis; Risk Factors; Vitamin D Deficiency

Cardiovascular disease is the leading cause of mortality in patients with end-stage renal disease (ESRD) and is attributed to a combination of traditional and non-traditional cardiovascular risk factors. In recent years, there has also been an increasing recognition of a very high prevalence of cardiovascular calcification in the ESRD population, including in patients receiving long-term peritoneal dialysis (PD). Numerous observational cohort studies have demonstrated the prognostic importance of cardiovascular calcifications in these patients. The mechanisms are not completely understood, but are likely multifactorial. The present article reviews the prevalence, clinical course, prognostic significance, and some contributing factors for vascular and valvular calcification in ESRD patients, including patients receiving PD therapy.

Topics: 1-Carboxyglutamic Acid; alpha-2-HS-Glycoprotein; Blood Proteins; Blood Vessels; C-Reactive Protein; Calcinosis; Calcium-Binding Proteins; Extracellular Matrix Proteins; Heart Valve Diseases; Heart Valves; Humans; Kidney Failure, Chronic; Matrix Gla Protein; Osteoprotegerin; Peritoneal Dialysis; Prevalence; Prognosis; Vascular Diseases

Experimental and clinical trials in the field of bone biology helped to clarify the role of receptors, which belong to the tumor necrosis factor family, such as osteoprotegerin and receptor activator of nuclear factor kappaB (RANK), in the regulation of bone remodeling. The ligand of the receptor activator of nuclear factor kappaB (RANKL) is a stimulator of bone resorption, while osteoprotegerin is the soluble "decoy" receptor to RANKL, protecting thereby bone from resorption. Pathological states of bone remodeling (like osteoporosis) are associated with imbalance in the activity of osteoprotegerin and the receptor activator of nuclear factor kappaB. Recent studies, however, also indicate that the osteoprotegerin/RANKL/RANK system has important roles in the regulation of the immune and vascular system as well. In this review we summarize the function and regulation of osteoprotegerin, its role in pathological states--primarily in cardiovascular diseases--and its relevance as a marker of cardiovascular risk. Finally, we present our prospective trial performed among the chronic dialyzed patients, where we examined the association between the cardiovascular mortality, osteoprotegerin levels and the arterial stiffness.

Topics: Aged; Analysis of Variance; Animals; Biomarkers; Blood Flow Velocity; Bone Diseases; Bone Remodeling; Calcinosis; Cardiovascular Diseases; Carotid Arteries; Female; Femoral Artery; Heart Rate; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Osteoprotegerin; Prospective Studies; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Renal Dialysis; Risk Assessment; Risk Factors; Time Factors; Vascular Diseases; Vascular Resistance; Vasodilation

In the last decade, the nephrology community has focused its attention on the main cause of morbidity and mortality in chronic renal failure patients: cardiovascular disease. In addition, recent studies pointed out that vascular calcification (VC) is a major cause of cardiovascular disease in the dialysis population. Interestingly, the pathogenesis of VC and soft tissue calcification in chronic kidney disease (CKD) has been extensively investigated. Nowadays we know that VC is associated not only with passive calcium phosphate deposition, but also with an active, cell-mediated process. To better understand the pathogenesis of VC in CKD, numerous regulatory proteins have been studied, because of their ability to inhibit mineral deposition in the vessels. We here examine the state of the art of those substances recognized as regulatory key factors in preventing VC in uremic conditions, such as fetuin A (alpha2-Heremans-Schmid glycoprotein), matrix gamma-carboxyglutamic acid protein, pyrophosphate, osteoprotegerin and bone morphogenetic protein. We conclude that at present it is too early to introduce these novel markers into clinical practice.

Topics: 1-Carboxyglutamic Acid; alpha-Fetoproteins; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Diphosphates; Humans; Kidney Failure, Chronic; Models, Biological; Osteoprotegerin; Risk Factors; Transforming Growth Factor beta; Uremia; Vascular Diseases

Atherosclerosis and vascular calcification often co-exist in chronic kidney disease (CKD) patients. Although the former has been recently recognized as an active inflammatory process, atherosclerosis-related calcification of the intima is still viewed as a passive epiphenomenon. Recent experimental data showed that ossification of the internal vascular wall might also be an active inflammatory process interrelated to atherosclerosis. Factors like RANKL (receptor activator of nuclear factor kappaB ligand), RANK and osteoprotegerin modulate vascular calcification and at the same time are involved in the process of atherosclerosis. Moreover, basic calcium phosphate crystals could interact with and activate monocytes-macrophages that produce proinflammatory cytokines capable of initiating - via endothelial activation and leukocyte adhesion - the atherosclerotic process. Thus, vascular calcification might be an active player and not simply an epiphenomenon in atherosclerosis. Should the above-mentioned data be confirmed in future studies, calcification of the internal vascular wall and atherosclerosis might be viewed and treated as tightly interconnected and linked by inflammation processes in CKD patients.

Topics: alpha-2-HS-Glycoprotein; Atherosclerosis; Blood Proteins; Calcinosis; Calcium Phosphates; Humans; Kidney Failure, Chronic; Lipoproteins, LDL; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Vascular Diseases

Vascular calcification is often encountered in advanced atherosclerotic lesions and is a common consequence of aging. Calcification of the coronary arteries has been positively correlated with coronary atherosclerotic plaque burden, increased risk of myocardial infarction, and plaque instability. Chronic kidney disease (CKD) patients have two to five times more coronary artery calcification than healthy age-matched individuals. Vascular calcification is a strong prognostic marker of cardiovascular disease mortality in CKD patients. Vascular calcification has long been considered to be a passive, degenerative, and end-stage process of atherosclerosis and inflammation. However, recent evidence indicates that bone matrix proteins such as osteopontin, matrix Gla protein (MGP), and osteocalcin are expressed in calcified atherosclerotic lesions, and that calcium-regulating hormones such as vitamin D3 and parathyroid hormone-related protein regulate vascular calcification in in vitro vascular calcification models based on cultured aortic smooth muscle cells. These findings suggest that vascular calcification is an actively regulated process similar to osteogenesis, and that bone-associated proteins may be involved in the development of vascular calcification. The pathogenesis of vascular calcification in CKD is not well understood and is almost multifactorial. In CKD patients, several studies have found associations of both traditional risk factors, such as hypertension, hyperlipidemia, and diabetes, and uremic-specific risk factors with vascular calcification. Most patients with progressive CKD develop hyperphosphatemia. An elevated phosphate level is an important risk factor for the development of calcification and cardiovascular mortality in CKD patients. Thus, it is hypothesized that an important regulator of vascular calcification is the level of inorganic phosphate. In order to test this hypothesis, we characterized the response of human smooth muscle cell (HSMC) cultures to inorganic phosphate levels. Our findings indicate that inorganic phosphate directly regulates HSMC calcification through a sodium-dependent phosphate transporter mechanism. After treatment with elevated phosphate, there is a loss of smooth muscle lineage markers, such as alpha-actin and SM-22alpha, and a simultaneous gain of osteogenic markers such as cbfa-1 and osteocalcin. Elevated phosphate may directly stimulate HSMC to undergo phenotypic changes that predispose to calcification, a

Topics: Alkaline Phosphatase; Bone and Bones; Calcification, Physiologic; Calcium; Calcium-Binding Proteins; Cell Differentiation; Disease Progression; Extracellular Matrix Proteins; Glycoproteins; Humans; Kidney Failure, Chronic; Matrix Gla Protein; Models, Biological; Osteoblasts; Osteoprotegerin; Phosphates; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Vascular Diseases

Patients with end-stage renal disease have greatly elevated risks of atherosclerotic disease. Vascular calcification in advanced atherosclerosis is a common feature in ESRD patients. Risk factors of atherosclerosis in ESRD patients are coronary risk factors such as hypertension, diabetes and hyperlipidemia and hyperphosphatemia. Bone associated proteins including osteopontin, matrix Gla protein and osteoprotegerin may be involved in the progression of atherosclerosis.

Topics: Arteriosclerosis; Calcium-Binding Proteins; Diabetes Complications; Diabetes Mellitus; Extracellular Matrix Proteins; Glycoproteins; Humans; Hyperlipidemias; Hypertension; Kidney Failure, Chronic; Matrix Gla Protein; Osteopontin; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Sialoglycoproteins

The abnormal metabolism of calcium and bone is one of the most common complications seen in chronic dialysis patients. The activity of PTH has been mainly assessed by intact PTH assay; however, recent data suggest that this assay may overestimate PTH activity by detecting 7-84 PTH fragments in addition to 1-84 PTH molecules(whole PTH). Another issue in this field is that higher levels of PTH are needed to maintain normal bone turnover in uremic patients. Accumulated osteoprotegerin in uremic serum may be responsible for this skeletal resistance to PTH.

Topics: Biomarkers; Bone and Bones; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Glycoproteins; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Osteoprotegerin; Parathyroid Hormone; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis; Uremia

Chronic renal failure patients on dialysis are at a high risk of death due to vascular calcification. This study aimed at investigating the effect of omega-3 fatty acids on the vascular calcification biomarkers fetuin-A and osteoprotegerin (OPG) in patients with chronic renal failure who are undergoing hemodialysis. This prospective, open-label, controlled, parallel study included 60 hemodialysis patients who were randomized to receive either omega-3 fatty acids capsule along with their standard care of treatment (omega-3 group) or their standard care of treatment only (control group). Serum levels of fetuin-A, OPG, calcium, phosphorus, hemoglobin, parathyroid hormone, blood urea nitrogen (BUN), albumin, serum creatinine (SCr), and serum triglycerides (TG) were measured at baseline and after six months of intervention and follow-up of both groups. Significantly increased levels of fetuin-A and OPG (p < 0.001) were observed in the omega-3 group six months after the intervention compared with the control group. Levels of TG, albumin, SCr, BUN, phosphorous, calcium, hemoglobin, and parathyroid hormone were not significantly different in the omega-3 group compared with the control group after six months of intervention. Our study concluded that omega-3 may have a clinically beneficial effect in decreasing cardiovascular events by increasing the levels of the protective vascular calcification inhibitors fetuin-A and osteoprotegerin in chronic renal failure patients who are undergoing hemodialysis.

Topics: Albumins; alpha-2-HS-Glycoprotein; Biomarkers; Calcium; Fatty Acids, Omega-3; Female; Humans; Kidney Failure, Chronic; Osteoprotegerin; Parathyroid Hormone; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Vascular Calcification

This study aimed to examine the impact of combined supplementation of fish oil (FO) with antioxidants like wheat germ oil (WGO) on mineral-bone and inflammatory markers in maintenance HD patients.. This randomized, double-blind, placebo-controlled trial involved 46 HD patients who were randomly assigned into two groups to receive daily 3000 mg of FO [1053 mg omega-3 fatty acids (ω-3 FAs)] plus 300 mg of WGO [0.765 mg vitamin E] or placebo for 4 months. Blood concentrations of hemoglobin (Hgb), white blood cells, mineral-bone parameters including serum calcium (Ca), phosphorus, calcium-phosphorus product, parathyroid hormone, alkaline phosphatase, and osteoprotegerin and serum concentrations of inflammatory markers including high-sensitivity C-reactive protein, ferritin, and uric acid were measured before and after the intervention.. Eighty-seven percentage of patients in each group completed the study. The mean serum Ca levels increased significantly in the supplemented group at the end of study (p = 0.0016), and this increment was also significant as compared to placebo group (p = 0.0418). No significant alterations were observed in the other measured parameters within each group during the study (as p values were >0.05).. FO plus WGO supplementation showed beneficial effect on serum Ca levels of HD patients without any statistically significant effect on other mineral-bone and inflammatory markers. Further investigations are required to confirm it.

Topics: Adult; Alkaline Phosphatase; Antioxidants; Biomarkers; C-Reactive Protein; Calcium; Dietary Supplements; Double-Blind Method; Drug Therapy, Combination; Fatty Acids, Omega-3; Female; Ferritins; Fish Oils; Hemoglobins; Humans; Kidney Failure, Chronic; Leukocyte Count; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Phosphorus; Plant Oils; Prospective Studies; Renal Dialysis; Uric Acid

Endothelial dysfunction marker, von Willebrand factor (vWF), is physically connected with osteoprotegerin (OPG) in the Weibel-Palade bodies. We aimed to compare the effect of unfractionated (UFH) and low-molecular-weight (LMWH enoxaparin) heparin used as anticoagulants during hemodialysis (HD) on plasma levels and relationships of OPG, soluble receptor activator of nuclear factor κB Ligand (sRANKL), and vWF.. Totally 21 clinically stable chronic HD patients were randomly assigned to either enoxaparin (n = 10) or UFH (n = 11) anticoagulation and followed prospectively for 12 weeks before crossing over to the alternate therapy for further 12 weeks. The OPG, RANKL, and vWF levels were measured at T0, T10, and T180 of HD session after each period of evaluation.. The baseline sRANKL level was higher under UFH treatment. Its over-HD level does not behave significantly different under enoxaparin and UFH treatment. Plasma OPG levels expressly changed during both enoxaparin (χ(2) analysis of variance [ANOVA] = 31.13, P < .016) and UFH (χ(2) ANOVA = 8.26, P = .016) anticoagulation, and its increment at T10 and T180 was significantly different between both the heparins. The main negative predictor of OPG concentration was the total cholesterol level (β = -.51, P = .025). von Willebrand factor concentration remained stable during UFH anticoagulation, whereas constant, no significant increments were noticed, under enoxaparin treatment. After 10 minutes of HD, especially under enoxaparin use, a positive correlation between OPG and vWF increase was noticed (P = .03, R = .45).. Impact of heparin on endothelial cells and simultaneously on OPG/RANK/RANKL axis reinforces the presumption of the pathophysiological linkage between bone mineralization and endothelial dysfunction in end-stage renal disease.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Cross-Over Studies; Female; Heparin; Heparin, Low-Molecular-Weight; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; RANK Ligand; Renal Dialysis; von Willebrand Factor

Patients treated with hemodialysis (HD) have an increased mortality, mainly caused by cardiovascular disease (CVD). Osteoprotegerin (OPG) is a glycoprotein involved in the regulation of the vascular calcification process. Previous studies have demonstrated that OPG is a prognostic marker of mortality. The aim of this study was to investigate if OPG was a prognostic marker of all-cause mortality in high-risk patients with end-stage renal disease and CVD.. We prospectively followed 206 HD patients with CVD. OPG was measured at baseline and the patients were followed for 2 years or until reaching the primary endpoint, i.e., all-cause mortality.. All-cause mortality during follow-up was 44% (90/206). High OPG was associated with increased mortality, using the first tertile as reference, with an unadjusted HR of 1.70 (CI 1.00 - 2.88) for the second tertile and HR of 1.63 (CI 0.96 - 2.78) for the third tertile. In a multivariate Cox-regression analysis age, CRP and OPG in both the second and third tertile were significantly associated with increased mortality In the unadjusted survival analysis, a test for trend of OPG yielded a p-value of 0.08; in the adjusted analyses, the p-value for trend was 0.03.. In a high-risk population of hemodialysis patients with previously documented cardiovascular disease, a high level of OPG was an independent risk marker of all-cause mortality.

Topics: Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Chi-Square Distribution; Denmark; Double-Blind Method; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Proportional Hazards Models; Prospective Studies; Renal Dialysis; Risk Assessment; Risk Factors; Secondary Prevention; Time Factors; Treatment Outcome; Up-Regulation

In patients with chronic kidney disease, vascular calcification contributes to increased cardiovascular (CV) morbidity and mortality. CV risk remains high after successful renal transplantation. Osteoprotegerin (OPG) is a glycoprotein, involved in the regulation of the vascular calcification process. Previous studies have shown that elevated OPG is predictive of mortality in high-risk populations. The aim of this study was to investigate the prognostic value of OPG for graft function, CV events and all-cause death, in a large transplant cohort.. OPG was measured at baseline in renal transplant recipients enrolled in the Assessment of Lescol in Renal Transplantation (ALERT) study, a randomized placebo-controlled intervention study comparing fluvastatin and placebo. Patients were followed for 6.7 years with evaluation of pre-specified end points, graft loss, graft function, CV events and death.. OPG was analysed in 1889 renal transplant recipients, with a mean value of 4.69 ± 1.85 pg/L. The number of renal and CV events increased by quartiles of OPG. In the multivariate analysis, OPG in the fourth as compared to first quartile was an independent predictor of graft failure or doubling of serum creatinine [hazard ratio (HR) 2.20 (1.56-3.11), P < 0.001], major CV events [HR 2.40 (1.58-3.64), P < 0.001], cardiac mortality [HR 2.80 (1.32-5.94), P = 0.007] and all-cause mortality [HR 2.31 (1.53-3.49), P < 0.001].. In a large cohort of kidney transplant patients with long-term follow-up, OPG was independently associated with renal events, CV events and mortality.

Topics: Adult; Aged; Anticholesteremic Agents; Biomarkers; Cardiovascular Diseases; Creatinine; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Graft Rejection; Humans; Indoles; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Osteoprotegerin; Prognosis; Risk Factors; Survival Rate; Vascular Calcification

The association between end-stage renal disease and cardiovascular mortality may be influenced through vascular alterations, in particular atherosclerosis and vascular calcification. The study goal was to assess the impact of each type of arterial intimal calcifications (AIC) and arterial medial calcifications (AMC), of osteoprotegerin (OPG), mineral metabolism markers and other features on all-cause and cardiovascular mortality in chronic hemodialysis patients.. Ultrasound was performed in 87 patients on the carotid and femoral arteries, and the severity of AIC and AMC was assessed calculating a score according to the extension of calcification. We analyzed the link between AIC, AMC, OPG, mineral markers and mortality after 6 years of follow-up.. The cutoff value for OPG determined using ROC was 4.9 pmol/l for all-cause and cardiovascular mortality. Patients with higher serum OPG levels presented higher mortality rates. Our study revealed that AIC, high OPG, low ankle-arm index, presence of diabetes, smoking status, and lack of arteriovenous fistula are associated with all-cause and cardiovascular mortality in univariate regression analysis. Multivariate analysis identified AIC scoring based on the segmentation method as an independent predictor of all-cause and cardiovascular mortality, along with increased OPG levels. AMC scoring was not a predictor of mortality.. Identifying and scoring AIC on ultrasound and measuring OPG levels, as a basis of the HD patient assessment may become valuable tools in clinical work, as these have an impact on death toll.

Topics: Atherosclerosis; Biomarkers; Humans; Kidney Failure, Chronic; Osteoprotegerin; Renal Dialysis; Vascular Calcification

Background Micro RNA -125b (miR-125b) has been shown to regulate vascular calcification ( VC ), and serum miR-125b levels are a potential biomarker for estimating the risk of uremic VC status. However, it is unknown whether clinical features, including chronic kidney disease-mineral bone disorder molecules, affect serum miR-125b levels. Methods and Results Patients receiving chronic dialysis for ≥3 months were recruited from different institutes. Serum miR-125b and chronic kidney disease-mineral bone disorder effectors, including intact parathyroid hormone, 25- OH -D, fibroblast growth factor-23, osteoprotegerin, and fetuin-A, were quantified. We used multivariate regression analyses to identify factors associated with low serum miR-125b levels and an area under receiver operating characteristic curve curve to derive optimal cutoffs for factors exhibiting close associations. Further regression analyses evaluated the influence of miR-125b on VC risk. Among 223 patients receiving chronic dialysis (mean age, 67.3 years; mean years of dialysis, 5.2), 54 (24.2%) had high serum miR-125b levels. Osteoprotegerin ( P=0.013), fibroblast growth factor-23 ( P=0.006), and fetuin-A ( P=0.036) were linearly associated with serum miR-125b levels. High osteoprotegerin levels independently correlated with high serum miR-125 levels. Adding serum miR-125b levels and serum osteoprotegerin levels (≥400 pg/mL) into models estimating the risk of uremic VC increased the area under receiver operating characteristic curve values (for models without miR-125b/osteoprotegerin, with miR-125b, and both: 0.74, 0.79, and 0.81, respectively). Conclusions Serum osteoprotegerin levels ≥400 pg/mL and serum miR-125b levels synergistically increased the accuracy of estimating VC risk among patients receiving chronic dialysis. Taking miR-125b and osteoprotegerin levels into consideration when estimating VC risk may be recommended.

Topics: Aged; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; MicroRNAs; Osteoprotegerin; Prospective Studies; Radiography; Radioimmunoassay; Renal Dialysis; Risk Factors; Uremia; Vascular Calcification

Aortic arch calcification (AoAC) is a fatal complication in dialysis. AoAC progression-related molecules in continuous ambulatory peritoneal dialysis (CAPD) remain unclear.. AoAC was estimated using plain chest radiography scoring (AoACS) in 30 CAPD patients (age 49.3 ± 13.4 years). AoAC progression was defined as increased AoACS on follow-up chest X-ray at the end of the study (progressors). Fibroblast growth factor-23 and osteoprotegerin (OPG) were measured.. Median follow-up was 38.5 months. Progressors were older, had shorter PD vintage, higher body mass index, and higher serum OPG levels (255.6 ± 109.2 pg/mL) than nonprogressors (183.4 ± 68.2 pg/mL; p = 0.0400). Progressors also showed higher pulse pressure (62.4 ± 20.0 mm Hg) and pulse wave velocity (1,909.9 ± 310.6 cm/s) than nonprogressors (48.5 ± 13.6 mm Hg; p = 0.0030 and 1,390.1 ± 252.8 cm/s; p = 0.0005, respectively).. AoAC progression was associated with increased aortic stiffness. OPG may be associated with AoAC progression in CAPD.

Topics: Adult; Aortic Valve; Disease Progression; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Peritoneal Dialysis; Vascular Calcification

Cardiovascular morbidity and mortality are highly prevalent in patients with end-stage renal disease, and osteoprotegerin (OPG) may be an important link between bone loss and vascular calcification. This study was conducted to evaluate the relationship between central arterial stiffness and serum OPG levels in hemodialysis (HD) patients.. Blood samples were collected from 120 HD patients, and the carotid-femoral pulse wave velocity (cfPWV) value was measured using a validated tonometry system. The cfPWV value of > 10 m/s was used to define the high artery stiffness group. Serum OPG levels were analyzed categorically into tertiles.. Of the 120 HD patients, 53 (44.2%) were defined as the high arterial stiffness group, who had higher values of systolic blood pressure (p = 0.038), serum calcium (p = 0.007), and OPG (p <  0.001) levels and a higher prevalence of diabetes mellitus (DM, p = 0.001). Increasing tertiles of serum OPG levels were significantly associated with greater height (p = 0.011), male gender (p = 0.008), higher cfPWV values (p = 0.020), and lower intact parathyroid hormone (iPTH, p = 0.049) levels. Multivariable linear regression analysis showed that cfPWV value was independently associated with DM (β = 1.83, p = 0.008) and increasing tertiles of serum OPG levels (β = 0.89 and 1.63 for tertile 2 and tertile 3, respectively, p for trend = 0.035) in HD patients. Multivariable logistic regression analysis revealed that, in addition to age, DM, low iPTH levels, and high serum calcium levels, increasing tertiles of serum OPG levels (OR = 5.34 for tertile 2; OR = 7.06 for tertile 3; p for trend = 0.002) were an independent predictor of high arterial stiffness in HD patients. Serum calcium levels positively correlated with cfPWV value only in the highest OPG tertile group (r = 0.408, p = 0.009).. A positive association was detected between serum OPG levels and central arterial stiffness in HD patients, and patients with high serum OPG levels may have greater influence of calcium load on central arterial stiffening.

Topics: Aged; Biomarkers; Carotid-Femoral Pulse Wave Velocity; Cross-Sectional Studies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Pulse Wave Analysis; Renal Dialysis; Vascular Stiffness

Tartrate-resistant acid phosphatase (TRACP)-5b and osteoprotegerin (OPG) are specific and sensitive markers of bone resorption in patients with rheumatoid arthritis (RA) and chronic kidney disease (CKD). The TRACP-5b level is associated with the severity of RA and CKD, while the OPG level is associated with the severity of coronary atherosclerosis and calcification, and can predict a poor outcome in patients with coronary artery disease (CAD). However, the impact of TRACP-5b on coronary atherosclerosis in CAD patients remains unclear.. A total of 71 CAD patients (57 men, 14 women; mean age: 69.0±9.7 years) and 28 age- and gender- matched healthy subjects were investigated. The number of diseased vessels (a marker of the severity of coronary atherosclerosis) and the Gensini score (a marker of the extent of coronary atherosclerosis), as well as the OPG and TRACP-5b levels were measured in CAD patients. The TRACP-5b levels were classified into quartiles.. The TRACP-5b levels were significantly higher in CAD patients than in healthy subjects. Patients with higher TRACP-5b levels had higher OPG levels and Gensini scores than those with lower TRACP-5b levels. Higher TRACP-5b levels were associated with an increased number of diseased vessels. A multivariate linear regression analysis showed that the OPG level and the number of diseased vessels or the Gensini score were significantly and independently associated with the TRACP-5b level.. These data indicate that the TRACP-5b level is significantly associated with the OPG level and with the severity and extent of coronary atherosclerosis in CAD patients.

Topics: Aged; Arthritis, Rheumatoid; Biomarkers; Calcinosis; Case-Control Studies; Coronary Artery Disease; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Smoking; Tartrate-Resistant Acid Phosphatase; Treatment Outcome

Fibroblast growth factor (FGF23), sclerostin, osteocalcin, and osteoprotegerin are important factors that control mineral bone metabolism. End-stage renal disease is associated with the pronounced dysregulation of mineral bone metabolism; however, the impact and clearance of mineral bone metabolism factors during dialysis remain largely undescribed.. In a cross-sectional study, 10 chronic hemodialysis patients were treated with hemodialysis for 8 h using a high-flux filter and a dialysate bath of 50% calculated total body water continuously recycled at a rate of 500 mL/min. Plasma and dialysate concentrations of FGF23, sclerostin, osteoprotegerin, and osteocalcin were measured at 1, 2, 4, 6, and 8 h permitting the estimation of dialysis clearance.. Clearance of FGF23 was 7.7 mL/min, of sclerostin was 7.6 mL/min, of osteoprotegerin was 1.2 mL/min, and of osteocalcin was 19.7 mL/min. Clearance of FGF23 was correlated to sclerostin and osteoprotegerin clearance and also to the ultrafiltration rate. Although, osteocalcin blood concentrations decreased during dialysis, they rebounded within 6 h. Overall, no significant changes in blood concentrations of the measure mineral bone metabolism factors were observed.. The intradialytic clearance of osteocalcin, FGF23, sclerostin, and osteoprotegerin occurs; however, only clearance of FGF23 is directly correlated with the ultrafiltration rate. The effects of dialytic clearance on mineral bone metabolism are, however, uncertain and intradialytic plasma concentrations of the studied substrates remained largely unchanged.

Topics: Adaptor Proteins, Signal Transducing; Aged; Bone Morphogenetic Proteins; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Genetic Markers; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteocalcin; Osteoprotegerin; Renal Dialysis

Topics: Biomarkers; Humans; Kidney Failure, Chronic; Osteoprotegerin; Renal Dialysis; Vascular Calcification

Arterial calcification (AC) is frequent in patients with end stage renal disease and is also considered a risk factor for later morbidity and mortality. However, long-term factors associated with the process are not well known. We analyzed the trends over time of biomarkers related with development and progression of AC in incident patients on peritoneal dialysis (PD).. We performed a prospective study with 186 patients on PD followed up for 1 year. We analyzed the progression of AC in the abdominal aorta and pelvic vessels by calcification score (CaSc), using16-cut computerized multidetector tomography at baseline and 1 year. Variables related with PD treatment, inflammation, and mineral metabolism were measured at baseline, 6, and 12 months of follow-up. Changes in biochemical variables were analyzed for their relationship with changes in AC.. Over 1 year, the number of patients with AC increased from 47 to 56%, and CaSc from 355 (interquartile range [IQR] 75-792) to 529 (IQR 185-1632). A total of 43.5% of patients remained free of calcification, 11.7% had new calcifications, and 44.8% had progression of calcification. Older age, diabetes, high systolic blood pressure, body mass index, cholesterol, and osteoprotegerin (OPG), as well as lower levels of albumin, serum creatinine, and osteocalcin, were associated with development of new, and rapid progression of, calcification. In multivariate logistic analysis, OPG remained the most significant (OR 1.27, 95% CI 1.11-1.47, p < 0.001).. OPG was the strongest risk factor associated with new development and rapid progression of AC in incident PD patients.

Topics: Adult; Age Factors; Aorta, Abdominal; Biomarkers; Diabetes Mellitus; Disease Progression; Female; Follow-Up Studies; Humans; Incidence; Kidney Failure, Chronic; Male; Mexico; Middle Aged; Osteoprotegerin; Peritoneal Dialysis; Prospective Studies; Risk Factors; Vascular Calcification; Young Adult

To assess whether serum osteoprotegerin (OPG) and/or fetuin-A predict mortality and cardiovascular (CV) morbidity and mortality in hemodialysis patients.. Multicenter, observational, prospective study that included 220 hemodialysis patients followed up for up to 6 years. Serum OPG and fetuin-A levels were measured at baseline and their possible association with clinical characteristics, CV risk biomarkers, carotid ultrasonographic findings, as well as their association with overall and CV mortality and CV events were assessed.. During a mean follow-up of 3.22 ± 1.91 years, there were 74 deaths (33.6%) and 86 new cardiovascular events. In the Kaplan-Meier survival analysis, the highest tertile of OPG levels was associated with higher overall mortality (p = 0.005), as well as a higher, although non-significant, incidence of CV events and CV mortality. In contrast, fetuin-A levels did not predict any of these events. OPG levels were directly associated with age, the Charlson comorbidity index (CCI), prevalent cardiovascular disease, carotid intima-media thickness, adiponectin, troponin-I and brain natriuretic peptide (BNP). OPG showed a negative correlation with left ventricular ejection fraction (LVEF) and phosphate levels. In the multivariate Cox proportional hazard analysis, all-cause mortality was associated with the highest tertile of OPG (HR:1.957, p = 0.018), age (HR:1.031, p = 0.036), smoking history (HR:2.122, p = 0.005), the CCI (HR:1.254, p = 0.004), troponin-I (HR:3.894, p = 0.042), IL-18 (HR:1.061, p < 0.001) and albumin levels (HR:0.886, p < 0.001). In the bootstrapping Cox regression analysis, the best cut-off value of OPG associated with mortality was 17.69 pmol/L (95%CI: 5.1-18.02).. OPG, but not fetuin-A levels, are independently associated with overall mortality, as well as clinical and subclinical atherosclerosis and cardiac function, in prevalent hemodialysis patients.

Topics: Aged; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Middle Aged; Mortality; Osteoprotegerin; Prospective Studies; Renal Dialysis

This cross-sectional study was designed to assess the relationship between vascular stiffness (VS) and bone-related proteins involved in the development of arteriosclerosis in patients on regular hemodialysis (HD).. 68 consecutive patients in stable clinical condition who received regular HD in the FMC Dialysis Center, Pécs were included. VS parameters (carotid-femoral pulse wave velocity - PWV, aortic augmentation index - AIx) were determined by applanation tonometry (SphygmoCor, AtCor Medical, Sidney) and the routine latoratory test were completed with measurements of osteocalcin (OC), osteopontin (OP) and osteoprotegerin (OPG) by using commercially available ELISA kits. 35 heathcare workers served as controls.. In patients on regular HD PWV markedly increased and there was several-fold elevation in the interrelated bone-specific proteins (OC, OP, OPG). PWV was found to be independently associated only with OC (β:-0.25, p<0.029) and age (r=0.411,p<0.000), but risk factors for arterial calcification had significant impact on OC (systolic blood pressure, hsCRP, BMI), OPG (age, BMI) and OP (LDL-cholesterol).. Except for OC, our results failed to document direct association of vascular lesion with OP and OPG, therefore their high circulating levels may be an epiphenomenon or they may have counter-regulatory role to attenuate the uremic calcification process.

Topics: Adult; Aged; Calcinosis; Case-Control Studies; Cross-Sectional Studies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteocalcin; Osteopontin; Osteoprotegerin; Pulse Wave Analysis; Renal Dialysis; Vascular Stiffness

Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is characterized by an increased fracture risk. Bone marrow mesenchymal stromal cells (BMSCs) may be involved in the pathogenesis of bone disease and, in view of their promising potential applications in bone tissue engineering, the effect of uremia on BMSCs regenerative potential represents a central issue. The present study evaluated in vitro the effect of a serum pool from hemodialysis patients on BMSCs to observe its influence on osteogenic differentiation. Besides alterations in spatial organization and cytotoxicity along with hyperproliferation, gene expression analysis suggested an impairment in the osteogenic differentiation. More importantly, Receptor activator of nuclear factor kappa-B ligand (RANKL) was upregulated with a mild reduction in osteoprotegerin levels. In summary, uremic environment seems to impair BMSCs osteogenic differentiation. Moreover BMSCs themselves may enhance osteoclastogenesis, feasibly contributing to the altered bone remodeling in CKD-MBD patients. J. Cell. Physiol. 232: 2201-2209, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Apoptosis; Bone Marrow Cells; Cell Cycle Checkpoints; Cell Differentiation; Cell Lineage; Cell Proliferation; Cell Shape; Cell Survival; Cells, Cultured; Cellular Microenvironment; Female; Gene Expression Regulation; Humans; Kidney Failure, Chronic; Male; Mesenchymal Stem Cells; Middle Aged; Osteogenesis; Osteoprotegerin; Phenotype; RANK Ligand; Renal Dialysis; Time Factors; Uremia

Osteoprotegerin (OPG) is a powerful inhibitor of osteoclast activity, and it plays an important role in bone metabolism. In hemodialysis (HD) patients, the relationship between OPG and bone mineral density (BMD) is important, but remains unclear yet. The study objective was to assess the OPG role related to uremic osteoporosis in HD patients.. This cross-sectional study has been realized on a cohort of 63 chronic HD patients.. elderly prevalent HD patients with an age over 55 years old.. previous bone disease or previous renal transplant; neoplasia; parathyroidectomy, hormone replacement therapy. The data regarding demographical and clinical characteristics, including treatments for mineral and cardiovascular complications, were recorded. Serum OPG and mineral markers levels were measured. BMD was assessed by calcaneus quantitative ultrasound; it measured broadband ultrasound attenuation, speed of sound (SOS) and stiffness index (STI).. The high OPG levels were associated with higher bone mineral density (OPG-SOS P = 0.003; R = 0.37; OPG-STI P = 0.03; R = 0.28). Malnutrition, anemia and advanced age correlated with bone demineralization. Males had higher bone density parameters than females. In patients treated with vitamin D (P = 0.005), the BMD was increased comparing to patients without these treatments.. OPG levels had directly correlated with bone mineral density parameters. Our study further confirms the critical role of OPG in the pathogenesis of uremic osteoporosis in ESRD. Whether the increased circulant OPG protect against bone loss in patients undergoing HD remains to be established.

Topics: Absorptiometry, Photon; Age Factors; Aged; Biomarkers; Bone Density; Case-Control Studies; Female; Follow-Up Studies; Humans; Incidence; Kidney Failure, Chronic; Male; Middle Aged; Osteoporosis; Osteoprotegerin; Renal Dialysis; Retrospective Studies; Risk Assessment; Survival Rate; Treatment Outcome

Wnt/β-catenin signaling pathway is thought to be implicated in the development of arterial stiffness and vascular calcification. As a Wnt signaling pathway inhibitor, it is interesting to investigate whether sclerostin or dickkopf-1 (DKK1) level is correlated with arterial stiffness in renal transplant (RT) recipients. Fasting blood samples were obtained for biochemical data, sclerostin, DKK1, and osteoprotegerin (OPG) determinations. In this study, we applied automatic pulse wave analyzer (VaSera VS-1000) to measure brachial-ankle pulse wave velocity and either sides of brachial-ankle pulse wave velocity value, which greater than 14.0 m/s was determined as high arterial stiffness. Among 68 RT recipients, 30 patients (44.1%) were in the high arterial stiffness group. Compared with patients in the low arterial stiffness group, patients in the high arterial stiffness group had higher prevalence of hypertension (P = 0.002), diabetes (P < 0.001), metabolic syndrome (P = 0.025), longer posttransplant duration (P = 0.005), higher systolic blood pressure (P < 0.001) and diastolic blood pressure (P = 0.018), and higher fasting glucose (P = 0.004), total cholesterol (P = 0.042), blood urea nitrogen (P = 0.020), phosphorus (P = 0.042), and sclerostin levels (P = 0.001). According to our multivariable forward stepwise linear regression analysis, age (β = 0.272, P = 0.014), phosphorus (β = 0.308, P = 0.007), and logarithmically-transformed OPG (log-OPG; β = 0.222, P = 0.046) were positively associated with sclerostin levels, and multivariate logistic regression analysis, sclerostin (odds ratio 1.052, 95% confidence interval 1.007-1.099, P = 0.024), and posttransplant duration (odds ratio 1.024, 95% confidence interval 1.004-1.045, P = 0.019) were the independent predictors of peripheral arterial stiffness in RT recipients. In this study, serum sclerostin level, but not DKK1, was proved to be involved in the pathogenetic process of peripheral arterial stiffness in RT recipients.

Topics: Adaptor Proteins, Signal Transducing; Adult; Ankle Brachial Index; Biomarkers; Bone Morphogenetic Proteins; Cross-Sectional Studies; Female; Genetic Markers; Humans; Hypertension; Intercellular Signaling Peptides and Proteins; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Osteoprotegerin; Postoperative Complications; Prospective Studies; Pulse Wave Analysis; Statistics as Topic; Taiwan; Vascular Calcification; Vascular Stiffness

Numerous biomarkers have been shown to associate with clinical endpoints in chronic kidney disease (CKD). There is limited evidence whether biomarkers improve risk prediction in relation to clinical outcomes. Our study investigates whether a small suite of key chronic kidney disease-mineral and bone disorder biomarkers could be used to enhance risk assessment in CKD.. Fetuin-A, fibroblast growth factor-23 and osteoprotegerin were measured on baseline plasma samples from 463 patients recruited to the Chronic Renal Insufficiency Standards Implementation Study. The biomarkers were analysed in relation to progression to end stage kidney disease, death and major cardiovascular events.. Over a median follow up of 46 months (interquartile range 21-69), fibroblast growth factor-23 was associated with risk for renal replacement therapy (hazard ratio (HR) 1.35, P = 0.05, 95% confidence interval (CI) 1.001-1.820), cardiovascular events (HR 1.74 P < 0.001, 95% CI 1.303-1.305) and death (HR 1.4 P = 0.005, 95% CI 1.109-1.767). Osteoprotegerin was associated with risk for death (HR 1.06, P = 0.03, 95% CI 1.006-1.117). There was no clear association between Fetuin-A and any of the clinical endpoints. The addition of biomarkers to risk models led to marginal improvement in model discrimination and reclassification.. Biomarkers are often associated with clinical endpoints, and we observed such associations in our study of patients with advanced CKD. However, the markers analysed in our study were of limited benefit in improving the prediction of these outcomes. Any extra information biomarkers may provide to improve risk prediction in clinical practice needs to be carefully balanced against the potential cost of these tools.

Topics: Aged; alpha-2-HS-Glycoprotein; Area Under Curve; Biomarkers; Cardiovascular Diseases; Disease Progression; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Osteoprotegerin; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; ROC Curve; Time Factors

To assess the osteoprotegerin (OPG) relationship with cardiovascular complications in hemodialysis (HD) patients.. The study included 87 HD patients. Clinical characteristics, ankle-arm index (AAI), OPG and mineral markers levels were recorded. Arterial intimal calcification (AIC) and arterial medial calcification (AMC) were registered.. OPG levels were increased in HD patients. Patients with AIC (p = 0.006)/ AMC (p = 0.01) had higher OPG levels. OPG did not have any relation with cardiovascular diseases. OPG correlated positively with age, increased HD vintage and inversely with albumin and AAI. OPG has not been a risk factor for VC or cardiovascular disease.. OPG rising could be a reaction in defense to vascular aggression, because OPG was associated with VC, but not with vascular disease.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Biomarkers; Blood Pressure; Calcinosis; Cardiovascular Diseases; Cross-Sectional Studies; Female; Humans; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Osteoprotegerin; Prospective Studies; Renal Dialysis; Risk Factors; Tunica Intima; Tunica Media; Young Adult

Bone-vessel interaction in chronic renal failure remains poorly understood and could be driven by bone remodeling factors including osteoprotegerin (OPG), fibroblast growth factor 23 (FGF23), parathormone and vitamin D. Only few data are available in renal transplantation. The aim of this study was to investigate the relationship between bone remodeling factors and large artery function in renal transplant patients.. 89 renal transplant patients were enrolled in this cross-sectional study. Carotid to femoral pulse wave velocity (PWV) and central augmentation index (AIx) were determined as an estimation of large artery function. Blood samples were collected for measurement of vascular risk markers. Independent predictors were identified by multivariate linear regression through backward feature selection using Akaike's information criteria.. At multivariate analysis, age (p < 0.001) and systolic arterial pressure (p = 0.003) were significantly associated with PWV but not AIx. In addition, both elevated blood concentrations of 1.25(OH)2 vitamin D (p = 0.013) and OPG (p = 0.047) were still significantly related to high PWV.. These results underline that age and mean arterial pressure are the main determinants of PWV following renal transplantation. Among bone remodeling biomarkers, plasma OPG and active vitamin D were the strongest determinants of arterial stiffness.

Topics: Adult; Age Factors; Arterial Pressure; Biomarkers; Bone Remodeling; Carotid Arteries; Female; Femoral Artery; Fibroblast Growth Factor-23; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Osteoprotegerin; Pulse Wave Analysis; Vascular Stiffness; Vitamin D

The objective of the study was to determine the relationship between common carotid artery intima-media thickness (CCA-IMT) and histologically assessed calcification of radial artery in relation to clinical features and laboratory markers of bone and mineral metabolism, inflammation, and oxidative stress in patients with stage 5 chronic kidney disease (CKD).. The study comprised 59 patients (36 hemodialyzed, 23 predialysis). CCA-IMT was measured by ultrasonography; the biochemical parameters examined were assessed using routine laboratory methods, ELISA micro-plate immunoassays and spectrophotometry. Fragments of radial artery obtained during creation of hemodialysis access were cryosectioned and stained for calcifications using von Kossa method and alizarin red.. Glucose, osteoprotegerin, pentraxin 3 and Framingham risk score significantly correlated with CCA-IMT. In multiple regression analysis, OPG positively predicted CCA-IMT. Radial artery calcifications were found in 34 patients who showed higher CCA-IMT (0.98 ± 0.13 vs 0.86 ± 0.14 mm; P = 0.006). Higher CCA-IMT values were also associated with more advanced calcifications. CCA-IMT and the presence of plaques in common carotid artery were positive predictors of radial artery calcifications, independent of dialysis status, Framingham risk score, CRP and Ca x Pi [OR for calcifications 2.19 (1.08-4.45) per 0.1 mm increase in CCA-IMT]. The presence of radial artery calcifications was a significant predictor of mortality, independent of dialysis status and Framingham risk score [HR 3.16 (1.03-9.64)].. In CKD patients, CCA-IMT examination can be used as a surrogate measure to assess the incidence and severity of arterial medial calcification which is associated with poor clinical outcome in these patients.

Topics: Adult; Aged; Aged, 80 and over; alpha-2-HS-Glycoprotein; Blood Glucose; C-Reactive Protein; Cardiovascular Diseases; Carotid Artery, Common; Carotid Intima-Media Thickness; Cohort Studies; Coronary Artery Disease; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Incidence; Inflammation; Insulin Resistance; Interleukin-6; Kidney Failure, Chronic; Logistic Models; Middle Aged; Multivariate Analysis; Osteocalcin; Osteopontin; Osteoprotegerin; Oxidative Stress; Radial Artery; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Serum Amyloid P-Component; Severity of Illness Index; Tunica Media; Vascular Calcification

Vascular calcification is common among patients undergoing dialysis and is associated with mortality. Factors such as osteoprotegerin (OPG), osteopontin (OPN), bone morphogenic protein-7 (BMP-7), and fetuin-A are involved in vascular calcification.. OPG, OPN, BMP-7, and fetuin-A were measured in blood samples from 602 incident dialysis patients recruited from United States dialysis centers between 1995 and 1998 as part of the Choices for Healthy Outcomes In Caring for ESRD Study. Their association with all-cause and cardiovascular mortality were assessed using Cox proportional hazards models adjusted for demographic characteristics, comorbidity, serum phosphate, and calcium. An interaction with diabetes was tested because of its known association with vascular calcification. Predictive accuracy of selected biomarkers was explored by C-statistics in nested models with training and validation subcohorts.. Higher OPG and lower fetuin-A levels were associated with higher mortality over up to 13 years of follow-up (median, 3.4 years). The adjusted hazard ratios (HR) for highest versus lowest tertile were 1.49 (95% confidence interval [95% CI], 1.08 to 2.06) for OPG and 0.69 (95% CI, 0.52 to 0.92) for fetuin-A. In stratified models, the highest tertile of OPG was associated with higher mortality among patients without diabetes (HR, 2.42; 95% CI, 1.35 to 4.34), but not patients with diabetes (HR, 1.26; 95% CI, 0.82 to 1.93; P for interaction=0.001). In terms of cardiovascular mortality, higher fetuin-A was associated with lower risk (HR, 0.85 per 0.1 g/L: 95% CI, 0.75 to 0.96). In patients without diabetes, higher OPG was associated with greater risk (HR for highest versus lowest tertile, 2.91; 95% CI, 1.06 to 7.99), but not in patients with diabetes or overall. OPN and BMP-7 were not independently associated with outcomes overall. The addition of OPG and fetuin-A did not significantly improve predictive accuracy of mortality.. OPG and fetuin-A may be risk factors for all-cause and cardiovascular mortality in patients undergoing dialysis, but do not improve risk prediction.

Topics: Adult; Aged; alpha-2-HS-Glycoprotein; Biomarkers; Bone Morphogenetic Protein 7; Chi-Square Distribution; Comorbidity; Diabetes Mellitus; Female; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Osteopontin; Osteoprotegerin; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Renal Dialysis; Risk Assessment; Risk Factors; United States; Vascular Calcification

Cardiovascular morbidity and mortality remains excessive in patients with chronic kidney disease. The association of vascular changes with regulators of extraosseous calcification in this patient population is still under investigation. The aim of the present study was to investigate the associations of the calcification inhibitor fetuin-A, and the anti-osteoclastic factor osteoprotegerin (OPG) with vascular pathology in chronic hemodialysis patients.. In this cross-sectional study including 81 stable chronic hemodialysis patients, we measured carotid-to-femoral pulse wave velocity (cfPWV) with applanation tonometry, reflecting arterial stiffness, and common carotid intima-media thickness (ccIMT), a surrogate of early atherosclerosis, as well as serum levels of fetuin-A and OPG. Co-morbidities, traditional cardiovascular risk factors, inflammatory markers and mineral-bone disease serology parameters were also recorded.. cfPWV correlated inversely with fetuin-A (r=-0.355, p=0.001) and positively with OPG (r=0.584, p<0.001). In multilinear regression analysis including age, gender, diabetes, cardiovascular disease, hypertension, pulse pressure, LDL, logCRP, both fetuin-A and OPG were independently associated with cfPWV (p=0.024 and p=0.041 respectively). ccIMT was negatively associated with fetuin-A (r=-0.312, p=0.005) and positively with OPG (r=0.521, p<0.0001); however these associations lost statistical significance after adjustment for age.. In chronic hemodialysis patients both fetuin-A and OPG levels are independently associated with arterial stiffness but not with early atherosclerotic vascular changes.

Topics: Adult; Aged; Aged, 80 and over; alpha-2-HS-Glycoprotein; Atherosclerosis; Biomarkers; Cross-Sectional Studies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Renal Dialysis; Vascular Stiffness; Young Adult

The aim of the present study was to compare levels of fetuin-A, osteoprotegerin (OPG), and heat shock protein (HSP)70 according to the stage of chronic kidney disease (CKD), as well as to evaluate the association between serum fetuin-A, OPG, and HSP70 concentrations with respect to vascular stiffness and calcification in hemodialysis (HD) patients.. We measured fetuin-A, OPG, and HSP70 in 35 healthy controls, 35 patients with stage 3 CKD, 35 patients with stage 4 CKD, and 81 HD patients. Using these data, we studied the association of fetuin-A, OPG, and HSP70 with clinical, biochemical, and vascular measures in HD patients.. Levels of OPG and HSP70 were higher and fetuin-A was lower in HD patients than in healthy controls. The cardio-ankle vascular index (CAVI) showed a positive correlation with OPG (r = 0.248, p = 0.040) and the OPG/fetuin-A ratio (r = 0.260, p = 0.031). The ankle-brachial index (ABI) showed a negative correlation with OPG (r = -0.245, p = 0.031) and the OPG/fetuin-A ratio (r = -0.267, p = 0.018). Intima-media thickness (IMT) showed a positive correlation with OPG (r = 0.273, p = 0.014) and the OPG/fetuin-A ratio (r = 0.269, p = 0.015). On stepwise multiple linear regression analyses, only the logarithmic function of the OPG/fetuin-A ratio was independently associated with CAVI (β = 13.325, SE = 6.247, p = 0.038).. Our results demonstrate that OPG and the OPG/fetuin-A ratio are correlated with increased vascular stiffness and IMT in HD patients. In addition, the OPG/fetuin-A ratio was independently associated with vascular stiffness in HD patients.

Topics: Aged; alpha-2-HS-Glycoprotein; Carotid Intima-Media Thickness; Female; HSP70 Heat-Shock Proteins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Renal Dialysis; Vascular Stiffness

Cardiovascular disease (CVD) is a major cause of death among chronic hemodialysis (HD) patients. Gender and age belong to its classical risk factors. OPG/RANK/sRANKL (Osteoprotegerin/ Receptor Activator of Nuclear Factor κB/ soluble Receptor Activator of Nuclear Factor κB Ligand) axis constitute a system connecting bone and vascular remodeling.. We aimed to evaluate the plasma levels of OPG, sRANKL and OPG/sRANKL ratio in 21 HD patients and 16 healthy volunteers in relation to gender, age and the other clinical parameters.. OPG and OPG/sRANKL ratio were significantly higher in HD patients than in controls whereas sRANKL was similar in both groups. Adjusted for gender, in controls OPG were higher in women whereas sRANKL did not differ between men and women. In HD group OPG and sRANKL were higher in women whereas OPG/sRANKL ratio was similar in both genders. Female patients compared to healthy women revealed 56% higher OPG concentration and 54% higher OPG/ sRANKL ratio. Comparison of male patients and controls revealed 61% higher level of OPG and 75% higher OPG/sRANKL ratio in HD group. Interestingly, OPG and OPG/sRANKL ratio positively correlated with age only in male patients. Contrary, the association between OPG/sRANKL ratio and age was negative in HD women.. Higher OPG levels in HD women comparing to age matched HD men indicate the necessity of more careful screening towards the presence of CVD and bone-mineral disorders. The negative association between age and OPG/ sRANKL ratio in HD women warrant in-depth study for thorough understanding of this complex interrelationship.

Topics: Adult; Age Distribution; Aged; Aged, 80 and over; Bone Diseases, Metabolic; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; RANK Ligand; Renal Dialysis; Risk Factors; Sex Distribution

The aim of the study was to assess the relationship between the advancement of secondary hyperparathyroidism and the concentrations of selected calcification markers, i.e. osteopontin (OPN), osteoprotegerin (OPG), osteocalcin (OC), fetuin-A as well as fibroblast growth factor-23 (FGF-23) in peritoneal dialysis patients (PD).. The study included 67 patients (36 male and 31 females) aged 52.9 years (19-75 years) with chronic kidney disease (CKD) on peritoneal dialysis therapy 30.4 +/- 24.2 months. BMI was calculated using Quetelet formula. Serum Pi, Ca, albumin, fibrinogen, iPTH were performed using standard laboratory methods, while the selected bone metabolism parameters: fetuin-A, OC, OPG, OPN and FGF-23 were measured based on commercially available ELISA kits.. Patients with high iPTH levels (> 300 pg/ml) had higher OC levels (median 68.5 ng/mL) comparing to patients with target iPTH, i.e. 100-300 pg/ mi (57.3 ng/mL; p = 0.003) and patients with low iPTH < 100 pg/ml (17.3 ng/mL; p < 0.0001). Also, OPN and FGF-23 concentrations were significantly higher in patients with high iPTH comparing to patients with target iPTH (1535 vs. 1001 ng/mL; p = 0.04 and 4952 vs. 702 RU/ mL; p = 0.02, respectively). Patients with increased Ca x P values (> 45 mg2/dl2) as compared with patients having lower Ca x P had higher FGF-23 (4308 vs. 678 RUlmL; p < 0.0001), higher OC (67.0 vs. 60.2 ng/mL; p = 0.049) and lower OPG concentrations (8.97 vs. 11.97 pmol/L; p = 0.02). OC strongly correlated with iPTH concentration (R = 0.78; p < 0.0001) and FGF-23 strongly correlated with Ca x P value (R = 0.74; p < 0.0001).. In peritoneal dialysis patients along with increment of IPTH concentrations and enchancement of calcium-phosphate imbalance, significantly rise concentrations of calcification markers such as: osteocalcin (OC), osteopontin (OPN), as well as fibroblast growth factor-23 (FGF-23).

Topics: Adult; Aged; alpha-2-HS-Glycoprotein; Biomarkers; Calcinosis; Calcium; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Osteocalcin; Osteopontin; Osteoprotegerin; Peritoneal Dialysis; Young Adult

Extra-skeletal calcification and disordered phosphate metabolism are hallmarks of chronic kidney disease-mineral bone disorder (CKD-MBD). Osteoprotegerin (OPG) and fibroblast growth factor 23 (FGF-23) are increased in chronic kidney disease (CKD) and have been associated with arterial and cardiac dysfunction and reduced survival. Troponin T (cTnT) is released from cardiac myocytes under conditions of stress and is predictive of mortality across a range of renal functions. However, the utility of this biomarker was formerly limited by the lower limit of assay detection. The introduction of a high-sensitivity assay has enabled more detailed study of myocyte stress below the previous limit of detection. We studied the association of mediators of CKD-MBD with arterial stiffness and also of these mediators and arterial stiffness with myocardial damage in patients with CKD stages 3-4.. OPG and FGF-23 were measured in 200 CKD stages 3-4 patients. cTnT was measured using a high-sensitivity assay. Aortic stiffness was assessed using aortic pulse wave velocity (APWV).. Mean age was 69 ± 11 years, mean systolic and diastolic blood pressure was 151 ± 22/81 ± 11 mmHg and renal function was 33 ± 11 mL/min/1.73 m(2). OPG, FGF-23, high-sensitivity troponin T (hs-cTnT) and APWV all correlated with renal function. After multivariate analysis, OPG and age remained independently associated with aortic stiffness. OPG and FGF-23 were independently associated with hs-cTnT in addition to other non-traditional risk factors (Model R(2) = 0.596).. We have shown that changes in bone mediators and phosphate metabolism induced by CKD are independently associated with vascular and cardiomyocyte dysfunction. Our findings suggest that cardiac dysfunction may be specifically associated with such abnormalities in addition to recognized increases in vascular stiffness.

Topics: Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Biomarkers; Bone Density; Bone Diseases; Cardiomyopathies; Cardiovascular Diseases; Cohort Studies; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Prognosis; Regression Analysis; Risk Assessment; Severity of Illness Index; Sex Factors; Survival Rate; Troponin T; Vascular Resistance

Secondary hyperparathyroidism (SHPT) is a common complication in chronic renal disease. Osteoprotegerin (OPG), an extracellular cytokine receptor secreted by osteoblasts, can promote bone formation by inhibiting the function of osteoclasts. Hemodialysis (HD) patients have elevated serum OPG levels. OPG secretion can be suppressed with high parathyroid hormone (PTH) levels. HD patients with refractory SHPT can benefit from parathyroidectomy (PTX) treatment, but the changes of serum OPG, bone turnover markers and bone mineral density (BMD) following PTX in HD patients remain unclear. In this study, patients on maintenance HD who received PTX for refractory SHPT (n = 28) were prospectively followed for 1 year. Serum intact PTH (iPTH), alkaline phosphatase (Alk-P), and OPG were measured serially; BMD was measured pre-PTX and at 1 year after PTX. After PTX, serum iPTH levels reduced profoundly. Serum Alk-P levels increased rapidly, peaking at 2 weeks post-PTX, while serum OPG levels gradually increased at 2 weeks after PTX and peaked at 2 months. BMD improved in both femoral neck (FN; cancellous and cortical bone) and lumbar spine (LS; cancellous bone). Higher baseline iPTH levels were associated with greater FN and LS BMD improvements at one year after PTX. The increment of serum OPG was correlated with the increase in LS BMD, implying that inhibition of osteoclastic bone resorption may improve BMD within the first year after PTX. These findings suggest that PTX removes the suppressive effects of high PTH on OPG secretion, resulting in the increased serum OPG levels that may contribute to BMD improvement.

Topics: Alkaline Phosphatase; Bone Density; Female; Femur Neck; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Lumbar Vertebrae; Male; Menopause; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Parathyroidectomy; Prospective Studies; Radiography; Renal Dialysis

In hemodialysis patients, 25-hydroxyvitamin D conversion to active 1,25-dihydroxyvitamin D by the kidneys is very limited. The expression of both vitamin D receptor and 1alpha-hydroxylase in cells of the immune system and in both osteoblasts and osteoclasts makes it possible that 25-hydroxyvitamin D could play an important role in both inflammation and bone metabolism acting in a autocrine and/or paracrine way in these patients.. Thirty-three hemodialysis patients not under vitamin D receptor agonist treatment were enrolled into the study. Serum levels of 25-hydroxyvitamin D, C-reactive protein (CRP), interleukin-6 (IL-6), receptor activator of nuclear factor-kappaB ligand (RANKL), and osteoprotegerin, as well as intact parathyroid hormone were assessed by immunoassays.. Regarding inflammation, 25-hydroxyvitamin D inversely correlated with both CRP and IL-6. Regarding bone metabolism, 25-hydroxyvitamin D was positively related to osteoprotegerin, but negatively to the RANKL. The latter could be the result of parathyroid hormone suppression by 25-hydroxyvitamin D, since 25-hydroxyvitamin D negatively correlated with parathyroid hormone, which in turn was positively related to RANKL.. Serum 25-hydroxyvitamin D is inversely correlated with markers of inflammation and may suppress osteoclastic activity in hemodialysis patients.

Topics: Biomarkers; Bone Resorption; C-Reactive Protein; Female; Humans; Inflammation; Interleukin-6; Kidney Failure, Chronic; Male; Middle Aged; Osteoclasts; Osteoprotegerin; Parathyroid Hormone; RANK Ligand; Renal Dialysis; Vitamin D

Osteoprotegerin (OPG) and fibroblast growth factor-23 (FGF23) are recognized as strong risk factors of vascular calcifications in non dialysis chronic kidney disease (ND-CKD) patients. The aim of this study was to investigate the relationships between FGF23, OPG, and coronary artery calcifications (CAC) in this population and to attempt identification of the most powerful biomarker of CAC: FGF23? OPG?. 195 ND-CKD patients (112 males/83 females, 70.8 [27.4-94.6] years) were enrolled in this cross-sectional study. All underwent chest multidetector computed tomography for CAC scoring. Vascular risk markers including FGF23 and OPG were measured. Logistic regression analyses were used to study the potential relationships between CAC and these markers. The fully adjusted-univariate analysis clearly showed high OPG (≥10.71 pmol/L) as the only variable significantly associated with moderate CAC ([100-400[) (OR = 2.73 [1.03;7.26]; p = 0.04). Such association failed to persist for CAC scoring higher than 400. Indeed, severe CAC was only associated with high phosphate fractional excretion (FEPO(4)) (≥38.71%) (OR = 5.47 [1.76;17.0]; p = 0.003) and high FGF23 (≥173.30 RU/mL) (OR = 5.40 [1.91;15.3]; p = 0.002). In addition, the risk to present severe CAC when FGF23 level was high was not significantly different when OPG was normal or high. Conversely, the risk to present moderate CAC when OPG level was high was not significantly different when FGF23 was normal or high.. Our results strongly suggest that OPG is associated to moderate CAC while FGF23 rather represents a biomarker of severe CAC in ND-CKD patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Calcinosis; Coronary Artery Disease; Cross-Sectional Studies; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Osteoprotegerin; Renal Dialysis

A high circulating osteoprotegerin (OPG) level may be a risk factor for vascular calcification and mortality in hemodialysis patients. OPG and pulse wave velocity (PWV) were measured at baseline in 151 normoalbuminemic, long-term (>3 years) Japanese hemodialysis patients who were prospectively followed for 6 years. In long-term normoalbuminemic Japanese hemodialysis patients, OPG levels were strongly linked with both arterial stiffness and worse outcome.. A high circulating OPG level is reported to be a risk factor for vascular calcification and mortality in Western chronic kidney disease (CKD) patients but it is not known if this is true for Japanese CKD patients, where a different risk profile may operate.. OPG and PWV were measured at baseline in 151 normoalbuminemic, long-term (>3 years) Japanese hemodialysis patients (median age 62 years) who were prospectively followed for 6 years.. OPG levels were associated in multivariate analysis with age, dialysis vintage, history of cardiovascular disease (CVD) and parathyroid hormone levels. C-reactive protein levels did not correlate with OPG. Patients with clinical history of CVD had significantly higher OPG levels and OPG levels were positively correlated to PWV, an index of arterial stiffness. These associations were independent of age, sex, dialysis vintage, and diabetes. During the follow-up period, 40 deaths, including 25 cardiovascular deaths, were recorded. In crude analysis, each unit of increase in OPG was associated with increased all-cause (hazard ratios 1.14, 95% confidence interval 1.08-1.20) and CVD mortality (1.14 [1.07-1.21]), which persisted after adjustment for age, sex, dialysis vintage, diabetes, and baseline CVD (1.12 [1.05-1.19] and 1.11 [1.02-1.19], all-cause and CVD mortality, respectively).. In long-term normoalbuminemic Japanese hemodialysis patients, with low prevalence of inflammation, OPG levels were strongly linked with both arterial stiffness and worse outcome.

Topics: Aged; Biomarkers; Blood Flow Velocity; Brachial Artery; Cardiovascular Diseases; Epidemiologic Methods; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Prognosis; Renal Dialysis; Serum Albumin; Vascular Stiffness

The aim of this prospective cohort study was to evaluate the progression of coronary artery calcification (CAC), and atherosclerosis in hemodialysis (HD) patients and to relate them to novel biomarkers, i.e. serum osteoprotegerin (OPG) and fibroblast growth factor 23 (FGF-23).. Forty-seven HD patients were followed up for 30 months or until death. Intima media thickness (CCA-IMT), atherosclerotic plaques and CAC were assessed at baseline and after 30 months. Serum mineral parameters, lipids, OPG and plasma FGF-23 were also measured.. At baseline, 70% HD patients presented detectable CAC. The patients without calcification at baseline remained calcification free at 30 months and presented lower serum OPG and FGF-23 than those with CAC. A 64.4% progression of CAC was observed in all patients with CAC at baseline. In parallel, a 13% increase in CCA-IMT was found. Both ΔCAC and ΔCCA-IMT correlated positively with baseline and follow-up serum OPG. The patients who died had significantly higher baseline CAC and serum OPG.. The plasma level of OPG could serve as a surrogate marker of progression of atherosclerosis and calcification in patients with end-stage renal disease. Therefore, the serum OPG may be a candidate biomarker of cardiovascular complications and poor outcome among dialysis patients.

Topics: Adult; Aged; Atherosclerosis; Biomarkers; Calcinosis; Cohort Studies; Coronary Artery Disease; Disease Progression; Female; Fibroblast Growth Factor-23; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Prospective Studies; Renal Dialysis

Premature vascular calcification (or rather ossification) significantly contributes to morbidity and mortality in patients with chronic kidney disease stage 5 (CKD-5) and is linked to dysregulation of bone remodelling proteins. Recent evidence of a cross-talk between bone and fat tissue urged us to investigate whether the calcification/ossification-associated factors osteoprotegerin (OPG) and alpha-2-HS-glycoprotein (AHSG) are expressed in human uremic subcutaneous adipose tissue (SAT) and if the expression differs from nonuremic SAT.. Abdominal SAT biopsies were obtained from 38 patients with CKD-5 [16 women, 58 (22-73) years old] during the surgical insertion of a peritoneal dialysis catheter and 20 controls [11 females, 56 (40-77) years old] undergoing elective hernia repair or laparoscopic cholecystectomy. Real-time polymerase chain reaction (PCR) quantifications were performed followed by immunohistochemical staining and serum protein concentration measurements. Relative mRNA expression and protein concentrations were evaluated together with clinical parameters. An additional 59 patients with CKD-5 were included for replication of statistical analyses.. OPG but not AHSG mRNAs were detected in SAT, which were also positively immunolabelled for OPG. OPG mRNA levels were reduced (P = ·0001) and serum OPG concentrations were elevated (P < 0·0001), both about twofold, in patients compared to controls. Circulating OPG increased in proportion to BMI.. Human SAT expresses OPG but not AHSG, and OPG expression is reduced in patients with CKD-5 when compared to controls, despite increased circulating protein levels.

Topics: Adipose Tissue; Adult; Aged; alpha-2-HS-Glycoprotein; Blood Proteins; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Polymerase Chain Reaction; Prospective Studies; Young Adult

To study the most frequent markers of mineral-bone metabolism in young hemodialysis (HD) patients in order to detect any metabolism changes that could lead to the atherosclerosis and extravascular calcification frequently observed in chronic kidney disease (CKD) patients and estimate their potential prognostic significance.. We measured serum levels of intact-PTH (iPTH), Osteoprotegerin (OPG), total soluble receptor activator of nuclear factor-κB ligand (sRANKL), tartrate-resistant acid phosphatase (TRAP-5b), osteocalcin (Oc), bone-specific alkaline phosphatase (BAP), calcium, phosphorus, 25(OH)D(3) and 1,25 (0H)(2)D(3) in young HD patients and controls. In comparison to controls, serum OPG, iPTH, BAP, phosphorus, and osteocalcin levels were higher whereas 25(OH)D(3) and 1,25(OH)(2)D(3) were lower in HD patients.. In conclusion, our results indicate that bone formation and resorption parameters are already altered in young HD subjects. These changes may lead to vascular calcifications and cardiovascular complications, given that elevated OPG levels predict cardiovascular events in HD patients. Furthermore, low levels of vitamin D metabolites have been associated with the presence of vascular calcification.

Topics: Acid Phosphatase; Adolescent; Adult; Alkaline Phosphatase; Atherosclerosis; Biomarkers; Bone and Bones; Bone Density; Calcifediol; Calcitriol; Calcium; Case-Control Studies; Humans; Isoenzymes; Kidney Failure, Chronic; Osteocalcin; Osteoprotegerin; Parathyroid Hormone; Phosphorus; Prognosis; RANK Ligand; Renal Dialysis; Tartrate-Resistant Acid Phosphatase; Young Adult

The aim of the study was to assess the factors potentially involved in coronary artery calcifications (CAC) in end-stage renal disease patients. 253 hemodialysis (HD) patients (92 females, 161 males), aged 62.5 +/- 13.5, who had been on HD treatment for at least 6 months, were enrolled in a cross-sectional study. Calcium-phosphate product (Ca x P), body mass index (BMI), fetuin-A, osteoprotegerin (OPG), osteopontin, transforming growth factor-beta1 (TGF-beta1), fibroblast growth factor-23 (FGF-23) and matrix Gla protein (MGP) were considered. CAC was assessed using multislice spiral computed tomography and calcium score was quantified by means of the Agatston score. The median calcium score was 364 Agatston (range 0-7,336). CAC was detected in 228/253 patients (90.1%). Multivariate regression analysis, adjusted for age and for dialysis vintage, showed that TGF-beta1, OPG and days with Ca x P >55 mg/dl are independent predictors of CAC, while MGP was shown to be a protective factor. Surprisingly, results showed that BMI was a protective factor too: the interpolation with cubic spline function revealed a significant reduction in calcium score in patients with a high BMI (>28). However, when diabetes was considered in the regression analysis, only OPG emerged as a predictor of a high CAC score. The interpolation with spline function continued to show a significant reduction in CAC score in nondiabetic and in diabetic patients with the highest BMI quartile. The protective effect of a high BMI on CAC might represent another example of inverse biology in dialysis patients but it needs to be further addressed in larger longitudinal studies.

Topics: Adult; Aged; Body Mass Index; Calcinosis; Calcium; Cardiomyopathies; Cross-Sectional Studies; Diabetes Mellitus; Female; Fibroblast Growth Factor-23; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Transforming Growth Factor beta1

Patients on hemodialysis (HD) frequently experience cardiovascular events associated with vascular calcification. We investigated the involvement of osteoprotegerin (OPG), an inhibitor of vascular calcification, in the incidence of cardiovascular events and mortality among new HD patients.. We conducted a prospective cohort study of the association of serum OPG levels with morbidity and mortality in subjects who became new HD patients between June 2000 and May 2006.. A total of 99 patients (age 58.9 +/- 14.6 years, 65 male, 34 female) were prospectively followed up for 41.5 +/- 20.2 months. During this period, 27 patients developed cardiovascular events and 12 died of causes related to cardiovascular disease. When divided into 2 groups according to OPG levels, the high OPG group showed a higher prevalence of cardiovascular morbidity and mortality compared with the low OPG group. Cox's proportional hazards analysis associated the new onset of cardiovascular events with the high OPG group (HR 2.88, 95% CI 1.09-7.62, p = 0.033). Furthermore, the high OPG group at the start of HD was significantly associated with older age, male gender and a high aortic calcification index.. Elevated levels of serum OPG in new HD patients may predict subsequent cardiovascular events.

Topics: Adult; Aged; Aged, 80 and over; Calcinosis; Cardiovascular Diseases; Cohort Studies; Female; Humans; Japan; Kaplan-Meier Estimate; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Osteoprotegerin; Proportional Hazards Models; Renal Dialysis; Young Adult

The influence of pre-dialysis chronic kidney disease (CKD) on bone is ill defined. Isolation of specific pathogenic mechanisms would improve the understanding and therapeutic options. We therefore investigated whether parathyroid dysfunction, altered vitamin D and hormonal status, or RANKL and OPG have an influence on bone mineral density (BMD) in patients with pre-dialysis renal failure.. 132 patients with chronic renal failure stage 1 - 5 (not yet on dialysis) were investigated in a cross sectional study. Osteoprotegerin (OPG), receptor activator of nuclear factor kB ligand (RANKL), parathyroid hormone (whole, intact and 7-84 fragment), bone markers, sex hormones, and vitamin D status were assessed together with femoral neck and trochanter z-score. Correlation and multivariate analyses were performed between the different parameters and BMD.. In the multivariate analysis a significant association was found between the femoral neck z-score and sRANKL (B = -0.45; p < 0.001), and OPG (B = 0.20; p < 0.05). A significant negative association was also found between the trochanter z-score and sRANKL (B = -0.32; p < 0.001). No associations were found between the trochanter z-score and OPG or the sRANKL/OPG ratio. The body mass index was the only additional marker associated with both FN z-score (B = 0.20, p < 0.05) and TR z-score (B = 0.20, p < 0.05). Neither markers of osteoblast nor osteoclast activity, or intact PTH, whole PTH, the PTH 7-84 fragment or vitamin D status were related to bone mineral density.. Our results demonstrate that the RANKL/RANK/OPG system is associated with bone mineral density in pre-dialysis chronic renal failure.

Topics: Adult; Aged; Biomarkers; Body Mass Index; Bone Density; Cross-Sectional Studies; Female; Femur; Follicle Stimulating Hormone; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Luteinizing Hormone; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; RANK Ligand; Testosterone; Vitamin D

We prospectively assessed the evolution of coronary artery calcification (CAC) and osteoprotegerin (OPG) levels after renal transplantation (RT). Eighty-three recipients were followed-up prospectively during 1 year. Blood was collected before (baseline) and after RT for determination of mineral metabolism parameters including OPG. CAC was measured by multidetector computed tomography at transplantation (baseline) and 1 year later. Progression of CAC was defined as a difference between the follow-up square-root transformed volume (SRV) and the baseline SRV >or= 2.5. By multivariate analysis, baseline OPG level, age and low LDL levels were significantly associated with baseline CAC. RT was accompanied by mineral metabolism improvement with a decrease of OPG from 955 [395-5652] to 527 [217-1818] pg/mL and parathyroid hormone from 94 [1-550] to 62 [16-410] pg/mL. Thirty-one percent of patients did not exhibit CAC at baseline. CAC diminished in 14.5%, stabilized in 59.2% and progressed in 26.3% of patients. Baseline CAC was associated with progression (OR 2.92 [1.02-8.36]). No significant association was found between OPG and CAC progression despite a higher baseline OPG level in progressors (1046 [456-3285]) vs. non-progressors (899 [396-5952] pg/mL). CAC at baseline, but not 1 year after RT, is independently associated with baseline OPG; posttransplant CAC progression is predicted by baseline CAC score.

Topics: Adult; Aged; Calcinosis; Coronary Artery Disease; Disease Progression; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Kidney Transplantation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Parathyroid Hormone; Predictive Value of Tests; Prospective Studies; Risk Factors; ROC Curve; Young Adult

Chronic kidney disease (CKD) is a complex disorder, which results in several complications involving disturbance of mineral metabolism. Periodontal disease is an infectious disease that appears to be an important cause of systemic inflammation in CKD patients. Periodontal disease is characterized by clinical attachment loss (CAL) caused by alveolar bone resorption around teeth, which may lead to tooth loss. Osteoprotegerin (OPG) is a key regulator of osteoclastogenesis. Polymorphisms are the main source of genetic variation, and single nucleotide polymorphisms (SNPs) have been reported as major modulators of disease susceptibility. The aim of this study was to investigate the association of a polymorphism located at position -223 in the untranslated region of the OPG gene, previously known as -950, with susceptibility to CKD and periodontal disease.. A sample of 224 subjects without and with CKD (in hemodialysis) was divided into groups with and without periodontal disease. The OPG polymorphism was analyzed by polymerase chain reaction and restriction fragment length polymorphism.. No association was found between the studied OPG polymorphism and susceptibility to CKD or periodontal disease.. It was concluded that polymorphism OPG-223 (C/T) was not associated with CKD and periodontal disease in a Brazilian population. Studies on other polymorphisms in this and other genes of the host response could help to clarify the involvement of bone metabolism mediators in the susceptibility to CKD and periodontal disease.

Topics: Adult; Aged; Brazil; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Periodontitis; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Young Adult

The bone-related peptide osteoprotegerin is produced by vascular cells and is involved in the process of vascular calcification. The aim of this study was to investigate the predictive value of plasma levels of osteoprotegerin in relation to mortality, cardiovascular events and deterioration in kidney function in patients with type 1 diabetes.. This prospective observational follow-up study included 397 type 1 diabetic patients with overt diabetic nephropathy (243 men; age [mean+/-SD] 42.1 +/- 10.6 years, duration of diabetes 28.3 +/- 9.9 years, GFR 67 +/- 28 ml min(-1) 1.73 m(2)) and a group of 176 patients with longstanding type 1 diabetes and persistent normoalbuminuria (105 men; age 42.6 +/- 9.7 years, duration of diabetes 27.6 +/- 8.3 years).. The median (range) follow-up period was 11.3 (0.0-12.9) years. Among patients with diabetic nephropathy, individuals with high osteoprotegerin levels (fourth quartile) had significantly higher all-cause mortality than patients with low levels (first quartile) (covariate-adjusted hazard ratio [HR] 3.00 [1.24-7.27]). High osteoprotegerin levels also predicted cardiovascular mortality (covariate-adjusted HR 4.88 [1.57-15.14]). Furthermore, patients with high osteoprotegerin levels had significantly higher risk of progression to end-stage renal disease than patients with low levels (covariate-adjusted HR 4.32 [1.45-12.87]). In addition, patients with high levels of plasma osteoprotegerin had an elevated rate of decline in GFR.. High levels of osteoprotegerin predict all-cause and cardiovascular mortality in patients with diabetic nephropathy. Furthermore, high levels of osteoprotegerin predict deterioration of kidney function towards end-stage renal disease.

Topics: Adult; Biomarkers; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Female; Glycated Hemoglobin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Survival Analysis

Numerous humoral factors are involved in the development of renal osteodystrophy, causing perturbations in bone mineral density (BMD) in patients with end-stage renal disease (ESRD). The RANKL/OPG cytokine system appears to mediate the effects of many of these factors on bone turnover, contributing to the pathogenesis of renal bone disease. The aim of this study was to evaluate the clinical and biochemical correlations of BMD measurements in patients on chronic hemodialysis. Fifty-four hemodialysis patients underwent measurement of BMD at the proximal femur and the lumbar spine (L2-L4). Intact parathyroid hormone (PTH), osteoprotegerin (OPG), sRANKL, and main bone biochemical markers were also measured in serum samples of all patients. BMD of the femoral neck was negatively correlated with OPG levels (r = 0.333, P = 0.014). OPG levels were significantly different among normal, osteopenic, and osteoporotic tertiles defined according to BMD of the femoral neck. The highest OPG levels were measured in the lowest T-score (osteoporotic) tertile and were higher than in the osteopenic and normal tertiles (P < 0.05). A threshold level for OPG at 21.5 pmol/l enabled the detection of osteoporotic patients with 76.5% sensitivity and 62.2% specificity. BMD values of trabecular bone-rich sites of the skeleton such as lumbar spine (L2-L4), trochanter, and Ward' s triangle were inversely correlated with total ALP levels (P < 0.05). Hemodialysis patients with low BMD of the femoral neck demonstrated higher OPG levels than patients with normal BMD. Those with lumbar spine (L2-L4), trochanteric, and Ward's triangle BMDs below the normal range presented higher total ALP levels. These results suggest that OPG and total ALP may be clinically useful markers in the detection of significant femoral neck and trabecular bone mineral deficit in hemodialysis patients, warranting further investigations.

Topics: Adult; Aged; Alkaline Phosphatase; Bone Density; Bone Diseases, Metabolic; Female; Femur Neck; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; RANK Ligand; Renal Dialysis

Vascular calcification occurs in the majority of patients with chronic kidney disease, but a subset of patients does not develop calcification despite exposure to a similar uraemic environment. Physiological inhibitors of calcification, fetuin-A, osteoprotegerin (OPG) and undercarboxylated-matrix Gla protein (uc-MGP) may play a role in preventing the development and progression of ectopic calcification, but there are scarce and conflicting data from clinical studies.. We measured fetuin-A, OPG and uc-MGP in 61 children on dialysis and studied their associations with clinical, biochemical and vascular measures.. Fetuin-A and OPG were higher and uc-MGP lower in dialysis patients than controls. In controls, fetuin-A and OPG increased with age. Fetuin-A showed an inverse correlation with dialysis vintage (P = 0.0013), time-averaged serum phosphate (P = 0.03) and hs-CRP (P = 0.001). Aortic pulse wave velocity (PWV) and augmentation index showed a negative correlation with fetuin-A while a positive correlation was seen with PWV and OPG. Patients with calcification had lower fetuin-A and higher OPG than those without calcification. On multiple linear regression analysis Fetuin-A independently predicted aortic PWV (P = 0.004, beta = -0.45, model R(2) = 48%) and fetuin-A and OPG predicted cardiac calcification (P = 0.02, beta = -0.29 and P = 0.014, ss = 0.33, respectively, model R(2) = 32%).. This is the first study to define normal levels of the calcification inhibitors in children and show that fetuin-A and OPG are associated with increased vascular stiffness and calcification in children on dialysis. Higher levels of fetuin-A in children suggest a possible protective upregulation of fetuin-A in the early stages of exposure to the pro-calcific and pro-inflammatory uraemic environment.

Topics: Adolescent; alpha-2-HS-Glycoprotein; Blood Flow Velocity; Blood Proteins; Blood Vessels; Calcinosis; Calcium-Binding Proteins; Cardiovascular Diseases; Case-Control Studies; Child; Child, Preschool; Extracellular Matrix Proteins; Female; Humans; Kidney Failure, Chronic; Male; Matrix Gla Protein; Osteoprotegerin; Renal Dialysis

Vascular calcifications in CKD are now linked to serum alterations of both divalent ions and calcification inhibitory proteins. Due to possible biochemical differences between dialysis (D) and transplantation (Tx), we examined the entity and severity of these biochemical modifications and of coronary artery calcium score separately in these two populations. We assayed, besides standard markers of inflammation, divalent ions and serum levels of fetuin, matrix Gla protein (MGP) and osteoprotegerin (OPG), in 51 Tx patients (age 45 +/- 12 years; 30 males, 21 females; previous D duration 4.8 +/- 4.2 years; Tx since 6.6 +/- 5.5 years; Cr 1.8 +/- 0.6 mg/dl) and in 49 D patients (age 49 +/- 14 years; 30 males,19 females; D duration 5.6 +/- 4.8 years). Additionally, coronary calcium score (AS) was evaluated by cardiac multi-slice CT. Compared with D patients, Tx patients had better values of divalent ions and inflammation markers, and lower prevalence (65 vs. 86%; p < 0.02) and severity (AS = 570 +/- 1,637 vs. 1,311 +/- 3,128; p < 0.008) of coronary calcification. In addition, a tendency toward normalization for all of the three calcification inhibitory proteins was evident. In both Tx and D, AS correlated with age and OPG (Tx: r(s) = 0.439, p < 0.001, and r(s) = 0.510, p < 0.0001; D: r(s) = 0.471, p < 0.001, and r(s) = 0.403, p < 0.005, respectively); in D patients, a correlation was present also with D duration (r(s) = 0.435; p < 0.002), other markers of inflammation and, notably, fetuin (r(s) = -0.442; p < 0.002). Regression analysis selected previous time on D in Tx patients (r(m) = 0.400; p < 0.004), and C-reactive protein and OPG in D patients (r(m) = 0.518; p < 0.004) as the most predictive parameters of AS. Discriminant analysis confirmed the major role of age and D duration in the appearance of AS and evidenced male gender as a distinct risk condition. At variance, Tx duration was never associated with AS. In conclusion, as compared to D, renal Tx patients show serum levels of calcification inhibition proteins and of divalent ions closer to normal. As this is associated with a lower prevalence and severity of AS, it is suggested that Tx antagonize the accelerating role of D in the progression of vascular calcification. Assessment of both coronary calcifications and serum levels of calcification inhibitory proteins may be of value to identify those subjects at higher risk of development and progression of vascular lesions, among whom males have the highest

Topics: 1-Carboxyglutamic Acid; alpha-Fetoproteins; Biomarkers; Calcinosis; Calcium; Calcium-Binding Proteins; Coronary Disease; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix Proteins; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Matrix Gla Protein; Middle Aged; Osteoprotegerin; Prognosis; Renal Dialysis; Severity of Illness Index; Tomography, X-Ray Computed

Osteoprotegerin (OPG) and receptor activator of the nuclear factor kappaB ligand (RANKL) constitute a complex system of mediators involved in the regulation of bone resorption process. Ghrelin, a growth hormone secretagogue, has been shown to modulate proliferation and differentiation of osteoblasts. The present study was carried out to evaluate the serum concentrations of OPG and sRANKL in children with chronic renal impairment (CRI) and on dialysis, and to establish a possible relationship between their serum levels and that of ghrelin.. 33 patients including 10 patients with CRI, 12 peritoneal dialysis (PD) and 11 hemodialysis (HD) patients and 22 healthy controls were enrolled into the study. OPG, sRANKL and ghrelin levels were studied with radioimmunoassay.. Serum OPG levels in CRI, PD and HD groups were significantly higher than the healthy controls (p = 0.002, p < 0.001, p < 0.001, respectively) whereas sRANKL levels were significantly lower than the healthy controls (p = 0.03, p = 0.01, p = 0.001, respectively). Ghrelin levels were significantly higher in CRI, PD and HD groups compared to healthy controls (p = 0.001, p < 0.001, p < 0.001, respectively). We observed a negative correlation between the sRANKL and OPG levels (r = -0.27, p = 0.04) as well as between sRANKL and ghrelin levels (r = -0.31, p = 0.02). OPG levels showed a positive correlation with ghrelin levels (r = 0.63, p < 0.001).. We found a lower RANKL bioactivity index in children with CRI and on dialysis. The mechanism and the role of elevated OPG and low sRANKL in uremia are unclear, but they might partly represent a compensatory mechanism to the negative balance of bone remodeling in renal bone disease in children. Additionally, we demonstrated for the first time that ghrelin and the RANKL/OPG system have a close relationship in CRF. Therefore, ghrelin may be of importance in mediating the effects of the RANKL/OPG system in renal bone disease.

Topics: Adolescent; Child; Child, Preschool; Female; Ghrelin; Humans; Kidney Failure, Chronic; Male; Osteoprotegerin; Peptide Hormones; Prognosis; RANK Ligand; Renal Dialysis; Reproducibility of Results; Risk Assessment; Risk Factors; Sensitivity and Specificity; Statistics as Topic

In the present study, we evaluated and compared serum markers of bone turnover in dialyzed patients with serum intact parathyroid hormone (iPTH) < 100 pg/mL (LBT group, n = 9), 100-150 pg/mL (MIX group, n = 6), and iPTH > 150 pg/mL (non-LBT group, n = 15). Laboratory parameters included iPTH; cyclase activating parathyroid hormone (CAP); osteoprotegerin (OPG); OPG ligand (OPGL); inorganic phosphates; total Ca, urea, and creatinine; alkaline phosphatase activity; and blood pH. Cyclase inactive parathyroid hormone (CIP) was calculated by subtraction of CAP from iPTH. When results were adjusted for sex, age, dialysis modality, and dialysis duration, only CAP and CIP were significantly different between the groups. For the LBT MIX, and non-LBT groups respectively, mean serum values for CAP were 20.3 pg/mL (range: 6.53-50.7 pg/mL), 79.3 pg/mL (range: 53.4-99.0 pg/mL), and 343.3 pg/mL (range: 102.1-887.9 pg/mL) and for CIP they were 7.74 pg/mL (range: 2.41-48.4 pg/mL), 50.2 pg/mL (range: 29.5-68.0 pg/mL), and 129.0 pg/mL (range: 62.4-399.0 pg/mL). In a selection of dialyzed patients, serum CAP and CIP concentrations--but not CAP/CIP ratio, OPG, OPGL, and OPGL/OPG ratio--can, like iPTH values, be used to categorize those suspected of having adynamic bone.

Topics: Biomarkers; Bone and Bones; Bone Remodeling; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Peritoneal Dialysis; RANK Ligand; Renal Dialysis

Osteoprotegerin (OPG) is a recently identified cytokine that acts as a decoy receptor for the receptor activator of nuclear factor-kappaB ligand (RANKL). OPG and RANKL have been shown to be important regulators of osteoclastogenesis. The aim of this study was to investigate the relationship between the OPG-RANKL system and bone mineral metabolism in patients with chronic renal failure (CRF).. Serum OPG, RANKL, osteocalcin, cross-linked c-telopeptide of type I collagen (ICTP), intact parathyroid hormone (PTH), bone alkaline phosphatase and cystatin C levels were measured in 40 chronic hemodialysis male patients and 32 age- and sex-matched healthy controls. Their lumbar spine bone mineral density (LS-BMD) was measured by dual energy X-ray absorptiometry.. Serum OPG, RANKL, PTH, bone alkaline phosphatase and cystatin C levels were significantly increased in patients with CRF. Serum OPG was positively correlated to serum RANKL and cystatin C. Positive correlations were found between serum RANKL and cystatin C and ICTP. LS-BMD was significantly lower in patients with CRF than in controls. In patients with CRF, LS-BMD was inversely correlated to serum RANKL and cystatin C, whereas it was positively correlated to serum OPG.. The OPG-RANKL system is involved in the pathogenesis and regulation of bone turnover in CRF. Circulating levels of OPG and RANKL may be useful markers to assess turnover renal osteopathies.

Topics: Adult; Biomarkers; Bone Density; Cystatin C; Cystatins; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Ligands; Male; Middle Aged; Osteocalcin; Osteoprotegerin; RANK Ligand

The processes involved in bone remodeling are under the control of a multitude of systemic and local factors. Receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) complex seems to be one of the major modulators of bone remodeling. In chronic renal failure, the cytokine systems involved in the regulation of bone turnover may be influenced, and are therefore likely to contribute to the pathogenesis of renal bone disease. The aim of the present study was the evaluation of RANKL/OPG complex in concert with other biochemical parameters in hemodialysis (HD) patients and the investigation of possible correlations between the serum levels of its components and several clinical parameters of these patients.. We measured serum levels of intact PTH (iPTH), total serum RANKL (sRANKL), osteoprotegerin (OPG), alkaline phosphatase, osteocalcin (OC), and tartrate-resistant acid phosphatase (TRAP) in 104 HD patients and in 40 healthy controls.. The average serum OPG level was significantly higher, whereas the average serum concentration of RANKL was nonsignificantly lower in patients on HD therapy than in age-matched healthy controls. Consequently, the mean sRANKL/OPG ratio was significantly lower in patients. Among HD patients, serum level of OPG increased significantly with aging and with a longer duration of hemodialysis. RANKL levels were inversely correlated with age nonsignificantly in the whole group of patients and significantly in the female subgroup (r=-0.322, p=0.035), whereas RANKL/OPG ratio declined significantly with age in the entire cohort of patients (r=-0.259, p=0.008). In addition, iPTH, OC, TRAP were significantly higher in female, whereas RANKL/OPG ratio was significantly higher in male than female patients.. Lower values of sRANKL/OPG ratio in HD patients, as well as the age and duration of HD dependent increase of serum OPG and the age-dependent decrease of sRANKL concentration especially in women cannot be explained by the elimination of renal clearance only. Alterations in sRANKL/OPG ratio might reflect a compensatory mechanism to modulate bone remodeling in these patients.

Topics: Acid Phosphatase; Adult; Age Factors; Aged; Aged, 80 and over; Alkaline Phosphatase; Biomarkers; Bone Remodeling; Case-Control Studies; Cohort Studies; Female; Humans; Isoenzymes; Kidney Failure, Chronic; Male; Middle Aged; Osteocalcin; Osteoprotegerin; RANK Ligand; Renal Dialysis; Sex Factors; Tartrate-Resistant Acid Phosphatase

Osteoprotegerin (OPG) acts by neutralizing the receptor activator of nuclear factor-kappaB ligand (RANKL), the primary mediator of osteoclast differentiation, function, and survival. We examined whether OPG could affect the bone loss associated with chronic kidney disease (CKD) in a rodent model of CKD and secondary hyperparathyroidism (SHPT). SHPT was induced in rats by 5/6 nephrectomy (5/6 Nx) and a 1.2% P/0.6% Ca(2+) diet. Starting 1 week after 5/6 Nx, rats were treated with vehicle (veh) or OPG-Fc (3 mg/kg, intravenously) every 2 weeks for 9 weeks. At baseline, 3, 6, and 9 weeks, blood was taken and bone mineral density (BMD) and bone mineral content (BMC) were assessed by dual-energy X-ray absorptiometry. Serum parathyroid hormone (sPTH) levels reached 912 pg/ml in 5/6 Nx rats vs. 97 pg/ml in shams at 9 weeks. OPG-Fc had no effect on sPTH or Ca(2+) levels throughout the 9-week study, indicating that SHPT was a renal effect independent of bone changes. At 3 weeks, 5/6 Nx-veh rats had osteopenia compared with sham-veh rats and 5/6 Nx-OPG-Fc rats had significantly higher percent changes in whole-body BMC, leg BMD, and lumbar BMD versus 5/6 Nx-veh rats. By 6-9 weeks, elevated sPTH was associated with reversal of bone loss and osteitis fibrosa in the proximal tibial metaphysis. OPG-Fc decreased this sPTH-driven high bone turnover, resulting in augmented thickness of proximal tibial trabeculae in 5/6 Nx rats. Thus, RANKL inhibition with OPG-Fc can block the deleterious effects of continuously elevated sPTH on bone, suggesting that RANKL may be an important therapeutic target for protecting bone in patients with CKD and SHPT.

Topics: Absorptiometry, Photon; Animals; Carrier Proteins; Disease Models, Animal; Glycoproteins; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Male; Membrane Glycoproteins; Osteoprotegerin; Parathyroid Hormone; RANK Ligand; Rats; Rats, Sprague-Dawley; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

As the main mineral reservoir, bone acts as a calcium (Ca) and phosphate buffering system. Accordingly, phosphate removal by haemodialysis (HD) might be theoretically influenced by bone turnover, as well as by the interaction of regulatory molecules, such as PTH and osteoprotegerin (OPG). The present study investigated the relationship between these variables and phosphate removal by HD.. Blood samples for serum Ca, phosphate, bicarbonate, intact PTH, PTH (1-84), bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, OPG and receptor activator of nuclear factor-kappaB ligand (RANKL) were obtained in 28 HD patients. Phosphate removal was measured by a continuous collection of the dialysate.. Pre-dialysis serum phosphate concentration is the critical factor in determining dialytic phosphate removal. However, multiple regression analysis reveals that phosphate removal is better explained by a combination of factors than by phosphate concentration alone. In this model, the PTH/OPG ratio is an additional positive factor, whereas age and vitamin D treatment are negative factors. Patients with pre-HD bicarbonate higher than 20 mEq/l had higher serum phosphate and, accordingly, higher phosphate removal; of interest, these individuals also have significant differences in RANKL/OPG. Mean (SD) OPG levels were significantly higher than that in the healthy population (16.2 (12.5) pmol/l; these values correlated with age (r = 0.4, P<0.04). Mean serum RANKL (1.03 (1.02) pmol/l) was within the range of normal individuals.. Dialytic phosphate removal has a crucial, direct relationship with pre-HD plasma phosphate levels. However, the phenomenon of phosphate removal is more precisely explained using a more complex relationship, defined by the interaction between serum phosphate, PTH/OPG, age and vitamin D administration. Serum RANKL levels are first reported in HD patients, and are not different from the normal population.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Biomarkers; Bone Demineralization, Pathologic; Case-Control Studies; Dialysis Solutions; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Phosphates; RANK Ligand; Renal Dialysis; Vitamin D

Bone turnover is regulated locally by osteoprotegerin (OPG) and receptor activator of NFkappaB ligand (RANK-L); it is not known how the circulating concentrations of these cytokines reflect renal osteodystrophy.. We measured serum OPG, RANK-L, parathyroid hormone (iPTH), collagen C-terminal cross-linked telopeptide (betaCrossLaps), and bone densitometry (BMD) in 79 patients with end-stage renal disease (ESRF) undergoing dialysis. A hand X-ray of these patients was also analyzed. Controls were 65 healthy subjects.. ESRF patients had high OPG and RANK-L levels; RANK-L was higher in hemodialysis than in peritoneal dialysis. OPG and RANK-L did not depend on iPTH. The bone markers were significantly increased and correlated with serum iPTH, but not with OPG or RANK-L; neither OPG nor RANK-L correlated significantly with BMD. OPG was significantly higher in patients with acro-osteolysis.. OPG and RANK-L serum concentrations do not strongly reflect bone status in ESRF. However, OPG was significantly higher in patients with acro-osteolysis.

Topics: Adult; Aged; Aged, 80 and over; Bone and Bones; Bone Density; Bone Remodeling; Carrier Proteins; Female; Glycoproteins; Hand; Humans; Kidney Failure, Chronic; Male; Membrane Glycoproteins; Middle Aged; Osteoprotegerin; Peritoneal Dialysis; Radiography; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis

Osteoprotegerin (OPG), a member of the TNF receptor superfamily is a natural inhibitor of osteoclastogenesis and important inhibitor of vascular calcification. The aim of the study was to estimate a correlation of serum OPG level and the other parameters calcium-phosphorus metabolism in children with chronic renal failure. Seventy four children with chronic renal insufficiency, 48 on conservative treatment (CRF) aged 13 +/- 3 years with creatinine clearance 45 +/- 21 ml/min/1.73m2 and 26 with end-stage renal disease (ESRD) aged 14 +/- 5 years were examined. The control group (K) consisted of 23 healthy children aged 10.8 +/- 3 years. In all children serum concentration of OPG, calcium (sCa), phosphorus (sP), PTH, CAP (cyclase activating PTH), CIP (cyclase inactive PTH) and osteocalcin (OC) were measured. OPG was determined by ELISA method (Biomedica), PTH and OC by IRMA (Duo-PTH, Scantibodies, USA and Osteo-Riact firm CIS, F).. The concentration of OPG was higher in ESRD group (3 +/-1.6 pmol/l) than in K (1.95 +/- 0.56 pmol/l), p<0.005. The concentration of OPG in CRF group (2.42 +/- 1.4 pmol/l) was not different from this in K and ESRD. The concentration of OPG did not correlate with serum creatinine level. In CRF group no correlation was found between OPG level and the other parameters, in group ESRD the significant correlation between OPG and OC was found (R=0.55, p=0.006). The level of OPG in children CRF + ESRD correlated with PTH concentration (R=0.27, p<0.03), CAP (R=0.29, p<0.02), CIP (R=0.23, p<0.05) and OC (R=0.25, P<0.04). In patients with higher PTH level (> 200 pg/ml) the higher correlations between OPG and PTH, CAP and CIP were found. No significant correlation between PTH and OPG in patients with lower PTH level (< 200 pg/ ml) was found. No significant correlation between OPG and OC in patients with lower and higher PTH was found.. The elevated levels of OPG in children with ESRD may reflect the higher bone turnover in these patients.

Topics: Adolescent; Adult; Calcium; Child; Child, Preschool; Humans; Kidney Failure, Chronic; Osteocalcin; Osteoprotegerin; Phosphorus

Vascular calcifications are an important risk factor for cardiovascular mortality and morbidity in patients with chronic renal failure. Osteoprotegerin, a soluble decoy receptor for receptor activator NFkB ligand, has emerged as an independent predictive factor of atherosclerosis and vascular calcification in hemodialysis patients. Sparse data are available on the evolution of osteoprotegerin after renal transplantation. The aim of this study was to follow the evolution of serum osteoprotegerin levels and biochemical risk factors after renal transplantation. Forty patients were included. Blood samples for analysis were collected before and 3 months after renal transplantation. Besides the expected diminution in calcium-phosphate product, we have shown an early normalization of osteoprotegerin (10.05 +/- 4.77 pmol/L to 4.59 +/- 2.26 pmol/L). This study demonstrates that kidney transplantation improves this risk factor for vascular calcifications. However, these preliminary results should be confirmed and extended by the follow-up of vascular calcifications in the long term.

Topics: Adult; Biomarkers; Calcinosis; Creatinine; Female; Humans; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Osteoprotegerin; Treatment Outcome

We evaluated serum markers of bone turnover (BT) in patients suspected to have low bone turnover (LBT) given their serum level of intact parathyroid hormone (iPTH). Studies were carried out in 30 dialyzed patients. In 9 patients, iPTH was below 100 pg/mL (LBT group), and in 21, it was above 100 pg/mL (non-LBT group). Other measured laboratory parameters included serum concentrations of cyclase inactivating parathyroid hormone (CAP), osteoprotegerin (OPG), OPG ligand (OPGL), inorganic phosphates, total calcium, creatinine, urea, serum alkaline phosphatase (ALP) activity, and blood pH. The LBT group showed significantly lower levels of iPTH (39.0 +/- 30.7 pg/mL), CAP (23.2 +/- 16.9 pg/mL), cyclase inactive parathyroid hormone (CIP: 15.8 +/- 15.0 pg/mL), and total ALP (83.9 +/- 26.2 IU/L) than did the non-LBT group (393 +/- 304 pg/mL, 268 +/- 216 pg/mL, 126 +/- 96 pg/mL, and 202 +/- 167 IU/L respectively). We observed no significant differences between the groups in the other examined parameters. When results were adjusted for sex, age, and dialysis modality and duration, differences remained significant only for iPTH and CIP. Our data indicate that a serum CIP concentration below 25 pg/mL has a significance similar to that of an iPTH concentration below 100 pg/mL in determining which dialyzed patients likely have LBT.

Topics: Biomarkers; Bone Remodeling; Calcium; Carrier Proteins; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Glycoproteins; Humans; Kidney Failure, Chronic; Male; Membrane Glycoproteins; Osteoprotegerin; Parathyroid Hormone; Phosphates; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis

The receptor activator of nuclear factor kappaB ligand (RANKL), produced by osteoblasts/stromal cells, is a member of the RANK/RANKL/OPG system, which regulates bone resorption by osteoclasts. Since RANKL and osteoprotegerin (OPG) production in bone is influenced by parathyroid hormone (PTH), we measured serum RANKL and OPG concentrations in haemodialysis (HD) patients, who commonly hypersecrete PTH. We aimed to determine if clinically demonstrated PTH-enhanced bone resorption is a consequence of increased RANKL synthesis.. RANKL, OPG, osteocalcin, intact PTH, bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase 5b and beta-CrossLaps (CTx) were measured in blood samples from 80 HD patients and 50 age-matched controls. HD patients were stratified to tertiles according to their serum PTH levels: 29.3-103.0, 109.7-263.0 and 262.0-1700.0 pg/ml in the first, second and third tertiles, respectively.. Mean serum RANKL levels were 1.6 times higher in HD patients than in age-matched controls (1.36+/-0.39 vs 0.83+/-0.70 pmol/l; P<0.001). All the measured bone markers significantly differed between patients and controls (P<0.001). Spearman's tests of correlation showed a statistically significant association of RANKL with PTH, osteocalcin and CTx (r=0.322, P=0.004; r=0.231, P=0.039; and r=0.230, P=0.040, respectively). Mean serum RANKL levels were significantly different between PTH tertiles (P = 0.003), but serum OPG levels were not (P=0.144). The highest RANKL levels were measured in the upper PTH tertile (1.54+/-0.39 pmol/l) and were significantly higher than in the middle or lower tertiles (1.27+/-0.42 and 1.23+/-0.26 pmol/l, respectively; P=0.003). Both of the measured bone-resorption markers, tartarate-resistant acid phosphatase 5b and CTx, as well as both bone formation markers, osteocalcin and bone-specific alkaline phosphatase were also significantly higher in the upper tertile, indicating that whole-bone remodelling is activated at high PTH and RANKL levels.. Serum RANKL levels were significantly higher in HD patients than in healthy age-matched controls. Moreover, RANKL levels were significantly higher in the upper PTH tertile, indicating enhanced RANKL synthesis in a PTH-dependent fashion. Thus, our clinical findings clearly support published in vitro studies that demonstrated a stimulating effect of PTH on RANKL synthesis. Therefore, the hypothesis that PTH increases bone resorption in HD patients through RANKL appears valid.

Topics: Acid Phosphatase; Adult; Aged; Alkaline Phosphatase; Bone Resorption; Carrier Proteins; Case-Control Studies; Collagen; Female; Glycoproteins; Humans; Isoenzymes; Kidney Failure, Chronic; Male; Membrane Glycoproteins; Middle Aged; Osteocalcin; Osteoprotegerin; Parathyroid Hormone; Peptide Fragments; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis; Tartrate-Resistant Acid Phosphatase

The mechanisms underlying the skeletal resistance to PTH in patients on chronic hemodialysis (CHD) are not yet fully clarified. Osteoprotegerin (OPG) and receptor activator of NF-kB ligand (RANK-L) modulate the genesis and activity of osteoclasts, however their role in renal osteodystrophy pathogenesis has not been clarified so far. The present study aimed to evaluate OPG and RANK-L serum levels in hemodialysis patients and whether OPG/RANK-L system could have a role in the skeletal resistance to PTH. In fasting blood samples obtained from 60 patients (36 males and 24 females) on CHD for at least 2 yr and from 40 healthy subjects of similar age and gender distribution as controls (CTRs), we measured serum OPG, RANK-L, bone alkaline phosphatase (B-ALP), N-terminal telopeptide of type I collagen (NTx), PTH(1-84), calcium and phosphate. In 30 of 60 hemodialysis patients, a blood sample was also drawn soon after the dialytic session. Serum levels of RANK-L, but not OPG, showed a slight but significant (p<0.05) decrease after the dialytic session. OPG resulted being about six times higher in CHD patients than in CTRs (38.7 +/- 16.2 vs 6.3 +/- 0.17 pg/ml), whereas RAN K-L serum levels were only slightly increased with respect to controls (0.88 +/- 0.47 vs 0.64 +/- 0.38 pmol/l). CHD patients showed serum PTH(1-84) and bone turnover higher than in CTRs. No correlation was found between OPG/RANK-L system and PTH or bone turnover markers. Instead, in the patients with high osteoclast activity (no.=21) OPG/RANK-L ratio was correlated (r=-0.41, p<0.01) with NTx serum levels, whereas in patients with decreased osteoclast activity (no.=39) no relationship was found. In conclusion, our findings showed that, although both OPG and RANK-L are accumulated in hemodialysis patients, only RANK-L and the balance between OPG and RANK-L seem to be related to osteoclast activity.

Topics: Aged; Alkaline Phosphatase; Bone and Bones; Calcium; Carrier Proteins; Collagen; Collagen Type I; Female; Glycoproteins; Humans; Kidney Failure, Chronic; Male; Membrane Glycoproteins; Middle Aged; Osteoclasts; Osteoprotegerin; Parathyroid Hormone; Peptides; Phosphates; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis

A newly identified cytokine, osteoprotegerin (OPG) appears to be involved in the regulation of bone remodeling. In vitro studies suggest that OPG, a soluble member of the TNF receptor family of proteins, inhibits osteoclastogenesis by interrupting the intercellular signaling between osteoblastic stromal cells and osteoclast progenitors. As patients with chronic renal failure (CRF) often have renal osteodystrophy (ROD), we investigated the role of osteoprotegerin (OPG) in ROD, and investigated whether there was any relationship between serum OPG, intact parathyroid (PTH) (iPTH), vitamin D, and trabecular bone. Serum OPG combined with iPTH might be a useful tool in the noninvasive diagnosis of ROD, at least in cases in which the range of PTH values compromises reliable diagnosis. Thirty-six patients on maintenance hemodiafiltration (HDF) and a control group of 36 age and sex matched healthy subjects with no known metabolic bone disease were studied. The following assays were made on serum: iPTH, osteocalcin (BGP), bone alkaline phosphatase, 25(OH)-cholecalciferol, calcium, phosphate, OPG, IGF-1, estradiol, and free testosterone. Serum Ca++, P, B-ALP, BGP, IGF-1, iPTH, and OPG levels were significantly higher in HDF patients than in controls, while DXA measurements and quantitative ultrasound (QUS) parameters were significantly lower. On grouping patients according to their mean OPG levels, we observed significantly lower serum IGF-1, vitamin D3 concentrations, and lumbar spine and hip bone mineral density in the high OPG groups. No correlation was found between OPG and bone turnover markers, whereas a negative correlation was found between serum OPG and IGF-1 levels (r=-0.64, p=0.032). Serum iPTH concentrations were positively correlated with bone alkaline phosphatase (B-ALP) (r=0.69, p=0.038) and BGP (r=0.92, p<0.001). The findings made suggest that an increase in OPG levels may be a compensatory response to elevated bone loss. The low bone mineral density (BMD) levels found in the high OPG group might have been due to the significant decrease in serum IGF-1 and vitamin D3 observed. In conclusion, the findings made in the present study demonstrate that increased OPG in hemodiafiltration patients is only partly due to decreased renal clearance. As it may partly reflect a compensatory response to increased bone loss, this parameter might be helpful in the identification of patients with a marked reduction in trabecular BMD.

Topics: Absorptiometry, Photon; Aged; Analysis of Variance; Biomarkers; Bone Density; Case-Control Studies; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Glycoproteins; Hemodiafiltration; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Probability; Prognosis; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reference Values; Risk Assessment; Sensitivity and Specificity

Coronary artery calcification (CAC) is thought to be associated with greater cardiovascular mortality in patients with end-stage renal disease than in nonuremic persons. The purpose of the present study is to assess the effects of etidronate, a synthetic analogue of pyrophosphate, on progression of CAC score.. The extent of CAC was evaluated by using multidetector spiral computed tomography. Repeated CAC score estimation was possible in 35 patients (29 men, 6 women). Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Serum osteoprotegerin (OPG) was measured by using enzyme-linked immunoassay. Serum etidronate was measured by means of the gas spectrometry technique using deuterium-labeled etidronate as internal standard.. Mean patient age was 63.2 +/- 8.2 (SD) years, and mean duration of dialysis therapy was 7.4 +/- 5.5 years. CAC score was estimated 3 times in each patient. After the second CAC score estimation, 35 patients were administered etidronate, 200 mg/d, for 14 days. This cycle was repeated 3 times every 90 days. CAC progression was significantly less pronounced during treatment with etidronate compared with the period before treatment was initiated. The median annualized absolute increase in calcified volume was 195.0 mm3 without treatment compared with -490.0 mm3 during treatment ( P < 0.01). Patients were divided into 2 groups based on changes in CAC score during etidronate treatment. Responders (n = 26) were patients whose CAC score decreased during therapy, and nonresponders (n = 9) were patients whose CAC score increased, even after etidronate therapy. Serum C-reactive protein values (0.18 +/- 0.13 mg/dL) in the responder group were greater than those (0.14 +/- 0.08 mg/dL) in the nonresponder group ( P = 0.013). Serum OPG levels decreased significantly during etidronate therapy (256.8 +/- 93.8 versus 245.0 +/- 83.0 pg/mL; P = 0.0161). Etidronate was well tolerated during the study. BMD values during etidronate therapy were not significantly changed from 0.941 +/- 0.125 to 0.968 +/- 0.246 g/cm2.. Results of the present study suggest that the extent of CAC may be suppressed by etidronate in association with a reduction in chronic inflammatory responses. They also suggest that a decrease in serum OPG concentrations by means of etidronate may be associated with changes in vascular calcification in dialysis patients.

Topics: Aged; Blood Chemical Analysis; Bone Density; Coronary Stenosis; Etidronic Acid; Female; Glycoproteins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis; Tomography, Spiral Computed

The aortic calcification index (ACI), estimated on abdominal computed tomographic scans, has been associated with the extent of arteriosclerosis in hemodialysis patients. However, the contribution of biochemical markers to the progression of vascular calcification in patients undergoing hemodialysis is not fully understood.. We examined the relationship between coronary risk factors; metabolic factors, including serum osteoprotegerin (OPG) concentration; and progression of vascular calcification in 26 dialysis patients.. Mean patient age was 52.6 +/- 8.7 (SD) years, and mean duration of dialysis therapy was 7.7 +/- 5.8 years. ACI was measured twice in each patient, and the mean interscan period was 4.9 +/- 0.3 years. Mean ACI changed from 22.2 +/- 24.2 to 33.9 +/- 28.8 overall, and mean change in ACI (DeltaACI) was 12.0 +/- 9.9. Patients were divided into 2 groups: slow progressors, with DeltaACI of 4.1 +/- 3.2 (n = 13), and rapid progressors, with DeltaACI of 19.8 +/- 7.9 (n = 13). Serum fasting glucose and CRP levels of rapid progressors were high, and their serum albumin and intact parathyroid hormone levels were low. Multiple regression analyses showed that serum OPG levels were independently associated with vascular calcification in the hemodialysis patients studied.. Rapid progression of vascular calcification was associated with dose of calcium carbonate prescribed and serum OPG concentration. The clinical significance of these observations remains to be determined.

Topics: Aortic Diseases; Arteriosclerosis; C-Reactive Protein; Calcinosis; Calcium; Calcium Carbonate; Disease Progression; Female; Glycoproteins; Humans; Kidney Failure, Chronic; Lipids; Longitudinal Studies; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Phosphorus; Prospective Studies; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis; Risk Factors

The hormone leptin is considered to have a role in the prevention of osteoporosis and probably acts on bone tissue through inhibition of osteoclasia. Its action has been attributed to interference in osteoprotegerin (OPG)/OPG-ligand equilibrium. Contradictory data also have been reported, casting doubts on the positive effect on bone mass of the hormone, at least in males. To date, the relation between serum leptin levels of dialysis patients and renal osteodystrophy, defined by histomorphometric and histodynamic parameters of bone, has not been studied.. The study included 46 hemodialysis patients (32 men, 14 women; age, 57.2 +/- 11.4 years). A transiliac bone biopsy after double-tetracycline labeling was performed for histological, histomorphometric, and histodynamic studies. Blood samples were drawn for leptin, intact parathyroid hormone (PTH), whole PTH (PTH1-84), OPG, bone alkaline phosphatase, calcium, phosphate, 25-hydroxycholecalciferol, and calcitriol. Serum leptin was measured by means of a radioimmunoassay.. Eighteen patients had mixed osteodystrophy (MO); 17 patients, hyperparathyroidism; 9 patients, adynamic bone disease (ABD); and 2 patients, osteomalacia. Aluminum histochemistry results were positive in 1 patient with ABD and 1 patient with MO. A sex difference was found in serum leptin levels (48.9 +/- 38 ng/mL in women and 12.2 +/- 13.2 ng/mL in men; P < 0.0002). In the entire population, lnleptin correlated significantly with body mass index (BMI; P < 0.01). SD score (SDS) leptin (adjusted for BMI, sex, and age) correlated inversely with PTH1-84 level and osteoclastic surface (OcS/BS; P < 0.05) and had a borderline correlation with bone formation rate. Correlations between leptin levels and other parameters were enhanced in men. SDS leptin correlated inversely with OcS/BS (P < 0.01), osteoclastic number (P < 0.01), and mineral apposition rate (P < 0.01). In addition, SDS leptin had a borderline inverse correlation with osteoblast surface (P < 0.06) and significant correlation with OPG level (P < 0.05). No difference was found in serum leptin levels between histological groups.. The reported data confirm the finding of a positive relation between serum leptin level and BMI and greater levels in women compared with men. Serum leptin level is connected to bone resorption and also bone formation, both inversely related to serum leptin levels. The decrease in osteoclasia that accompanies increasing serum leptin levels does not seem to be related to an enhanced OPG effect because it was accompanied by decreased OPG levels. Low-turnover bone disease does not appear to be caused by increased serum leptin levels. The nature of the interrelation between serum leptin and PTH1-84 levels requires further study.

Topics: Aged; Biomarkers; Body Mass Index; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Glycoproteins; Humans; Hyperthyroidism; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Osteomalacia; Osteoprotegerin; Parathyroid Hormone; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Renal Dialysis; Sex Factors; Statistics as Topic

Recently identified soluble circulating osteoprotegerin (OPG), a member of tumor necrosis factor receptor family, is the osteoclastogenesis inhibitory factor (OCIF). It acts as a "decoy" receptor for receptor activator of NF-kappaB ligand (RANKL) and antagonises RANKL/RANK activity. This way OPG exerts the protective effect on bone, which is also important in hyperparathyroidism. The studies measuring OPG levels in secondary hyperparathyroidism have shown contradictory results and inconsistent conclusions. The aim of our work was to evaluate OPG levels in hemodialysis patients and their correlation with the intensity of bone turnover, bone formation and bone resorption. Serum OPG levels, bone alkaline phosphatase activity (bALP) and beta-CrossLaps (CTx) were measured in a control group (n = 20, age 30+/-6.7 years) and in two groups of dialysis patients: the first group with serum intact parathyroid hormone (iPTH) concentration below 200 pg/ml (n = 28, age 62.6+/-14.8 years) and the second group with iPTH concentration above 200 pg/ml (n = 16, age 63.7+/-14.8 years). Compared to controls, serum OPG levels were 6.4-fold higher in dialysis patients. OPG levels in patients with high PTH were approximately 1.2-fold higher than in the low-PTH group. OPG correlated weakly with bALP (r = 0.277, p = 0.153), as well as with CTx (r = 0.018, p = 0.929) in the low-PTH group, and there was an insignificant negative correlation in the high-PTH group (r = -0.145, p = 0.593 and r = -0.219, p = 0.416, respectively). In conclusion, 6.4-fold increase in OPG might protect bone against intensive bone loss in hemodialysis patients, but this increase is probably not mediated by the increased bone formation; rather, it seems to be the consequence of the imbalance of bone kinetics in renal disease. The precise role of OPG in the pathogenesis of renal osteodystrophy remains unknown and establishing it requires further studies.

Topics: Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Chronic Kidney Disease-Mineral and Bone Disorder; Collagen; Female; Glycoproteins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Peptide Fragments; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis

Numerous growth factors and cytokines are known to modulate bone turnover. An important, recently discovered complex involved in osteoclastogenesis is the osteoprotegerin/osteoprotegerin-ligand (OPG/OPGL) cytokine complex, which is produced by osteoblasts. Many factors, including parathyroid hormone (PTH), appear to affect bone turnover through this pathway. In this disorder, the role of the OPG/OPGL system in the pathogenesis of renal osteodystrophy, a disease with either low or high bone turnover, has not been investigated so far.. Thirty-nine chronic haemodialysis patients had bone biopsies, including histomorphometric and histodynamic examinations. In addition, the following serum biochemistry parameters were measured: serum OPG, intact PTH, PTH 1-84, total PTH, osteocalcin, total and bone alkaline phosphatases, 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol.. On average, serum OPG levels were above the normal range. They were lower in adynamic bone disease (ABD) patients, than in patients with predominant hyperparathyroidism (HP) or mixed osteodystrophy (MO). Significant negative correlations were found between serum OPG and PTH levels, and between serum OPG and parameters of bone resorption (ES/BS) and bone formation (ObS/BS and BFR/BS) in HP and MO patients with PTH values < or =1000 pg/ml. For intact PTH levels < or =300 pg/ml, serum OPG was significantly lower in the group with ABD than in those with HP or MO (P<0.05).. In renal osteodystrophy the OPG/OPGL system is involved in the regulation of bone turnover induced by PTH. The determination of serum OPG levels could be of use in the diagnosis of low turnover bone disease, at least in association with PTH levels < or =300 pg/ml.

Topics: Aged; Bone and Bones; Bone Remodeling; Bone Resorption; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Glycoproteins; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Dialysis

Skeletal resistance to parathyroid hormone (PTH) is one of the major abnormalities underlying bone diseases in uremia, the mechanism of which has not yet been fully elucidated. Osteoclastogenesis inhibitory factor (OCIF), or osteoprotegerin, is a natural decoy receptor for osteoclast differentiation factor (ODF), produced by osteoblasts in response to PTH. To elucidate the kinetics and roles of OCIF in chronic renal failure, serum OCIF levels were measured in 46 predialysis patients and 21 dialysis patients by means of enzyme-linked immunosorbent assay (ELISA). Serum OCIF levels in predialysis patients increased as renal function declined (OCIF = 1.178 + 0.233 x creatinine; r2 = 0.413; P < 0.0001). Twenty-four-hour creatinine clearance and 1/OCIF in predialysis patients showed a clear positive correlation and a straight line regression (1/OCIF = 0.443 + 0.004 x creatinine clearance; r2 = 0.425; P < 0.0001). In dialysis patients, serum OCIF levels were significantly elevated (5.18 +/- 1.48 ng/mL) to a level that would inhibit 50% osteoclast formation in vitro. These findings suggest that OCIF accumulates in serum of patients with renal dysfunction. Because serum levels of OCIF with the ability to bind ODF in vitro (active OCIF) correlated well with those of OCIF detected by standard ELISA (active OCIF = 0.251 + 0.877 x OCIF; r2 = 0.829; P < 0.0001), OCIF accumulated in serum may be a candidate uremic toxin responsible for the skeletal resistance to PTH seen in chronic renal failure. Further studies with serum parameters and bone histological evaluation are needed to assess this possibility.

Topics: Aged; Aged, 80 and over; Biological Assay; Bone Resorption; Carrier Proteins; Enzyme-Linked Immunosorbent Assay; Female; Glycoproteins; Humans; Kidney Failure, Chronic; Male; Membrane Glycoproteins; Middle Aged; Osteoclasts; Osteoprotegerin; Parathyroid Hormone; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Regression Analysis; Renal Dialysis