osteoprotegerin and Kidney-Diseases

Ligands and receptors of the tumor necrosis factor (TNF) superfamily regulate immune responses and homeostatic functions with potential diagnostic and therapeutic implications. Kidney disease represents a global public health problem, whose prevalence is rising worldwide, due to the aging of the population and the increasing prevalence of diabetes, hypertension, obesity, and immune disorders. In addition, chronic kidney disease is an independent risk factor for the development of cardiovascular disease, which further increases kidney-related morbidity and mortality. Recently, it has been shown that some TNF superfamily members are actively implicated in renal pathophysiology. These members include TNF-related apoptosis-inducing ligand (TRAIL), its decoy receptor osteoprotegerin (OPG), and TNF-like weaker inducer of apoptosis (TWEAK). All of them have shown the ability to activate crucial pathways involved in kidney disease development and progression (e.g. canonical and non-canonical pathways of the transcription factor nuclear factor-kappa B), as well as the ability to regulate cell proliferation, differentiation, apoptosis, necrosis, inflammation, angiogenesis, and fibrosis with double-edged effects depending on the type and stage of kidney injury. Here we will review the actions of TRAIL, OPG, and TWEAK on diabetic and non-diabetic kidney disease, in order to provide insights into their full clinical potential as biomarkers and/or therapeutic options against kidney disease.

Topics: Animals; Biomarkers; Cytokine TWEAK; Diabetic Nephropathies; Humans; Kidney; Kidney Diseases; Osteoprotegerin; TNF-Related Apoptosis-Inducing Ligand

Background Osteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease ( CVD ) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear. Methods and Results Three independent reviewers systematically searched PubMed, EMBASE , and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high CVD risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow-up of 4.2 years, 4066 CVD events were recorded. In a random-effects meta-analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12-1.50; P<0.001; I

Topics: Acute Coronary Syndrome; Angina Pectoris; Biomarkers; Cardiovascular Diseases; Comorbidity; Diabetes Mellitus; Heart Diseases; Humans; Kidney Diseases; Myocardial Infarction; Myocardial Revascularization; Osteoprotegerin; Risk; Stroke

Vascular calcification in chronic kidney disease (CKD) patients is associated to increased mortality. Osteoprotegerin (OPG) is a soluble tumor necrosis factor (TNF) superfamily receptor that inhibits the actions of the cytokines receptor activator of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL) by preventing their binding to signaling receptors in the cell membrane. OPG-deficient mice display vascular calcification while OPG prevented calcification of cultured vascular smooth muscle cells and protected kidney cells from TRAIL-induced death. OPG may be a biomarker in patients with kidney disease. Circulating OPG is increased in predialysis, dialysis and transplant CKD patients and may predict vascular calcification progression and patient survival. By contrast, circulating OPG is decreased in nephrotic syndrome. In addition, free and exosome-bound urinary OPG is increased in human kidney disease. Increased urinary OPG has been associated with lupus nephritis activity. Despite the association of high OPG levels with disease, experimental functional information available suggests that OPG might be protective in kidney disease and in vascular injury in the context of uremia. Thus, tissue injury results in increased OPG, while OPG may protect from tissue injury. Recombinant OPG was safe in phase I randomized controlled trials. Further research is needed to fully define the therapeutic and biomarker potential of OPG in patients with kidney disease.

Topics: Animals; Humans; Kidney Diseases; Muscle, Smooth, Vascular; Osteoprotegerin; Recombinant Proteins; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Vascular Calcification

Recent years brought the discovery of new members of TNF receptor superfamily - osteoprotegerin/receptor activator of nuclear factor-kappaB and its ligand (OPG/RANK/RANKL) system as regulator of bone remodeling. Further studies showed its involvement in control of vascular and immune system. Animal studies' results confirm the OPG/RANK/RANKL role in pathogenesis of vascular calcifications and osteoporosis. Human studies, especially in patients with chronic kidney disease (CKD), have brought many conflicting data. Understanding of exact contribution of each molecule creating this axis may be crucial for diagnosis and treatment of CKD complications involving renal osteodystrophy and vascular calcification. In this review we try to summarize recent knowledge and OPG/RANK/RANKL role in patient with chronic kidney diseases.

Topics: Humans; Kidney Diseases; Nephrology; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

The mortality rate is extremely high in chronic kidney disease (CKD), primarily due to the high prevalence of cardiovascular disease (CVD) in this patient group. Apart from traditional Framingham risk factors, evidences suggest that nontraditional risk factors, such as inflammation, oxidative stress, endothelial dysfunction, and vascular calcification also contribute to this extremely high risk of CVD. Disturbance in the mineral metabolism, especially in the ions of Ca and PO4, are linked to enhanced calcification of blood vessels. Although the mechanism(s) of this enhanced calcification process are not fully understood, current knowledge suggests that a large number (and an imbalance between them) of circulating promoters and inhibitors of the calcification process, that is, fetuin-A (or alpha 2-Heremans-Schmid glycoprotein, AHSG), matrix-Gla protein (MGP), osteoprotegerin (OPG), osteopontin (OPN), bone morphogenetic proteins (BMPs), and inorganic pyrophosphate (PPi), are involved in the deterioration of vascular tissue. Thus, an imbalance in these factors may contribute to the high prevalence of vascular complications in CKD patients. Among these mediators, studies on fetuin-A deserve further attention as clinical studies consistently show that fetuin-A deficiency is associated with vascular calcification, all-cause and cardiovascular mortality in CKD patients. Both chronic inflammation and the uremic milieu per se may contribute to fetuin-A depletion, as well as specific mutations in the AHSG gene. Recent experimental and clinical studies also suggest an intriguing link between fetuin-A, insulin resistance, and the metabolic syndrome.

Topics: alpha-2-HS-Glycoprotein; Blood Proteins; Bone Morphogenetic Protein 7; Calcinosis; Calcium-Binding Proteins; Cardiovascular Diseases; Chronic Disease; Extracellular Matrix Proteins; Humans; Inflammation; Kidney Diseases; Matrix Gla Protein; Metabolic Syndrome; Osteopontin; Osteoprotegerin; Vascular Diseases

Topics: Anorexia Nervosa; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Female; Glycoproteins; Humans; Kidney Diseases; Male; Multiple Myeloma; Osteitis Deformans; Osteoprotegerin; Prostatic Neoplasms; Reagent Kits, Diagnostic; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reference Values; Specimen Handling; Urinary Bladder Neoplasms

Both cardiovascular calcification and autonomic dysfunction are frequently encountered in hemodialysis patients. We aimed to investigate the relationship between cardiovascular calcification and heart rate variability (HRV) and their influence on long-term outcome.. Seventy-eight hemodialysis patients underwent echocardiogram and radiography of the pelvis and hands to identify valvular and vascular calcification. HRV was evaluated using a commercial machine.. Based on the average, the patients were divided into higher and lower subgroups of high frequency (HF) and low frequency (LF) respectively. Patients with higher LF were younger and were found to have a lower proportion of diabetes. Their hemoglobin, albumin, and bone morphogenic protein (BMP)-7 levels were significantly higher and both high-sensitive C-reactive protein (hs-CRP) and osteoprotegerin levels were lower (all p < 0.05). In patients of the higher HF group, the proportion of diabetes was lower but they were found to have higher levels of BMP-7 and lower levels of hs-CRP, interleukin-6 (all p < 0.05). Significantly higher LF and HF were noted in patients without vascular calcification, but only hand artery (HA) calcification was negatively correlated with both LF and HF in multivariate analysis. Low LF and high hs-CRP were the independent predictors of mortality. Coexistence of low LF band and HA calcification was associated with the worse outcome.. Abnormal autonomic nervous function was closely related to inflammation and mortality in hemodialysis patients. Calcification of HA was associated with autonomic dysfunction and patients with lower autonomic tone and HA calcification had the highest mortality rate in this population.

Topics: Adult; Aged; Aged, 80 and over; Autonomic Nervous System Diseases; Bone Morphogenetic Protein 7; C-Reactive Protein; Cohort Studies; Diabetic Nephropathies; Electrocardiography; Female; Heart Rate; Humans; Interleukin-6; Kidney Diseases; Male; Middle Aged; Osteoprotegerin; Pelvis; Predictive Value of Tests; Prospective Studies; Renal Dialysis; Vascular Calcification

Abdominal Aortic Aneurysm (AAA) is multifactorial disease with unknown ethiology. Among the theories on the pathogenesis of AAA are some ge. netic factors, infections, disorders in connective tissue (collagenosis), arteriosclerosis, inflammation, incorrect immune response (autoimmunity). It was discovered that crucial for AAA development is intense inflammatory reaction combined with high proteolytic activity. Recent evidence confirmed the association between osteopontin (OPN) and osteoprotegerin (OPG) levels and cardiovascular diseases and arterio. sclerosis. The aim of this work was assessment of plasma levels of OPN and OPG in the group of the patients with AAA and correlation of results with clinical parameters, "classical" risk factors for development of AAA, arteriosclerosis and morbidity. The reference group consist of the patients with Leriche Syndrome (LS). The OPG level was assessed in plasma and OPN levels were assessed in plasma and urine. Plasma OPG levels were higher in AAA group than in LS group (difference not statistically significant, p = 0.0549). It was statistically significant positive correlation between plasma OPN levels and CRP levels in the groups of AAA and LS patients. It was not any association between plasma OPG and OPN levels and abdominal aortic diameter. Plasma OPG levels correlated positively with the existence of coronary artery disease in AAA patients. Insignificant, but higher levels of this protein were found also in a group of AAA patient with myocardial infarction. In LS group we found statistically significant positive association between plasma OPG levels and patient with stroke. However, in AAA patients with incidence of stroke, we found higher plasma levels of OPN. Interestingly, there was not any association between OPN levels in the urine and clinical parameters, risk factors and morbidity, including kidney diseases. inflammatory role of OPN and depicts better reflection of inflammatory reaction of OPN than OPG in both group of patients. Plasma OPG levels in AAA patients are more associated with coronary artery disease than with peripheral artery disease, what is characteristic for LS patients. Lack of association of urine OPN levels with above mentioned parameters suggest minor importance of this urine protein in clinical condition evaluation of patients with AAA and advanced arteriosclerosis.

Topics: Aged; Aortic Aneurysm, Abdominal; Arteriosclerosis; Biomarkers; Comorbidity; Coronary Artery Disease; Female; Humans; Kidney Diseases; Male; Middle Aged; Osteopontin; Osteoprotegerin; Risk Factors; Stroke

Vascular calcification is associated with increased cardiovascular mortality in chronic hemodialysis patients. This prospective study investigated the relationship between serum osteoprotegerin, receptor activator of NF-κB ligand, inflammatory markers, and progression of coronary artery calcification score.. Seventy-eight hemodialysis patients were enrolled. Serum IL-1β, IL-6, TNF-α, osteoprotegerin, receptor activator of NF-κB, fetuin A, and bone alkaline phosphatase were measured by ELISA. Coronary artery calcification score was measured two times with 1-year intervals, and patients were classified as progressive or nonprogressive.. Baseline and first-year serum osteoprotegerin levels were significantly higher in the progressive than nonprogressive group (17.39±9.67 versus 12.90±6.59 pmol/L, P=0.02; 35.17±18.35 versus 24±11.65 pmol/L, P=0.002, respectively). The ratio of serum osteoprotegerin to receptor activator of NF-κB ligand at 1 year was significantly higher in the progressive group (0.26 [0.15-0.46] versus 0.18 [0.12-0.28], P=0.004). Serum osteoprotegerin levels were significantly correlated with coronary artery calcification score at both baseline (r=0.36, P=0.001) and 1 year (r=0.36, P=0.001). Importantly, progression in coronary artery calcification score significantly correlated with change in serum osteoprotegerin levels (r=0.39, P=0.001). In addition, serum receptor activator of NF-κB ligand levels were significantly inversely correlated with coronary artery calcification scores at both baseline (r=-0.29, P=0.01) and 1 year (r=-0.29, P=0.001). In linear regression analysis for predicting coronary artery calcification score progression, only baseline coronary artery calcification score and change in osteoprotegerin were retained as significant factors in the model.. Baseline coronary artery calcification score and serum osteoprotegerin levels were significantly associated with progression of coronary artery calcification score in hemodialysis patients.

Topics: Adult; Aged; Biomarkers; Chi-Square Distribution; Chronic Disease; Coronary Artery Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation Mediators; Kidney Diseases; Linear Models; Male; Middle Aged; Osteoprotegerin; Prospective Studies; RANK Ligand; Renal Dialysis; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Turkey; Vascular Calcification

Vascular calcification is frequent in patients with chronic kidney disease. Osteoprotegerin (OPG, a soluble factor which blocks osteoclast differentiation) has recently been implicated in the genesis of vascular calcification. Given that OPG can bind the pro-apoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), we hypothesized that the TRAIL protein is involved in the formation of vascular calcification both in vitro and in vivo. Using an immunohistochemical approach, we evaluated TRAIL and OPG expression on aortic valves slides from non-uremic and uremic wild type and apolipoprotein knockout (Apo E(-/-) ) mice. We also tested the in vitro effects of TRAIL on cultured primary human vascular smooth muscle cells (hVSMC). We further assayed serum soluble TRAIL (sTRAIL) levels in hemodialysis patients and correlated them with vascular calcification scores. Our results demonstrated that: (i) TRAIL and OPG were expressed inside the atheroma plaque in non-uremic ApoE(-/-) mice, but not in wild type mice; and (ii) uremia enhanced the expression levels. TRAIL enhanced the phosphate-induced mineralization of hVSMCs in a dose-dependent manner. In clinical terms, we demonstrated that sTRAIL is depressed in the sera of hemodialysis patients, but was not correlated with vascular calcification. Our results suggest that TRAIL may be involved in the formation of vascular calcification in certain experimental settings; however, its role in chronic kidney disease patients requires further evaluation.

Topics: Aged; Animals; Apolipoproteins E; Calcinosis; Cells, Cultured; Chronic Disease; Disease Models, Animal; Female; Humans; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Muscle, Smooth, Vascular; Osteoprotegerin; Plaque, Atherosclerotic; Renal Dialysis; TNF-Related Apoptosis-Inducing Ligand; Uremia

Osteoprotegerin (OPG), receptor activator of the nuclear factor κB ligand (RANKL) and fibroblast growth factor-23 (FGF-23) play a central role in renal osteodystrophy. We evaluated OPG/RANKL and FGF-23 levels in 51 children with chronic kidney disease (CKD) [n = 26 stage 3 or 4 (CKD3-4) and n = 25 stage 5 (CKD5)] and 61 controls. Any possible association with intact parathyroid hormone (iPTH) and bone turnover markers was also investigated. The OPG levels were lower in the CKD3-4 group (p < 0.001) and higher in the CKD5 group (p < 0.01) than in the controls, while RANKL levels did not differ. The FGF-23 levels were higher in both patient groups (p < 0.0001), while the levels of phosphate and iPTH were higher only in the CKD5 group (p < 0.0001). There were independent positive correlations between OPG and RANKL (β = 0.297, p < 0.01) and FGF-23 (β = 0.352, p < 0.05) and a negative correlation with the bone resorption marker TRAP5b (β = -0.519, p < 0.001). OPG was positively correlated with iPTH (R = 0.391, p < 0.01). An independent positive correlation between FGF-23 and phosphate (β = 0.368, p < 0.05) or iPTH (β = 0.812, p < 0.0001) was noted. In conclusion, we found that higher OPG levels in patients with CKD stage 5 correlated with the levels of RANKL, FGF-23, iPTH, and TRAP5b. These findings may reflect a compensatory mechanism to the negative balance of bone turnover. High FGF-23 levels in early CKD stages may indicate the need for intervention to manage serum phosphate (Pi) levels.

Topics: Acid Phosphatase; Analysis of Variance; Biomarkers; Bone Remodeling; Case-Control Studies; Child; Child, Preschool; Chronic Disease; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Greece; Humans; Isoenzymes; Kidney Diseases; Male; Osteoprotegerin; Parathyroid Hormone; Phosphates; RANK Ligand; Regression Analysis; Severity of Illness Index; Tartrate-Resistant Acid Phosphatase

Chronic kidney disease-mineral and bone disorder (CKD-MBD) has been proposed to be the replacement of renal osteodystrophy by the Organization of Kidney Disease: Improving Global Outcomes since 2005 because the mineral disorder is not confined to the skeleton in CKD. Accordingly, laboratory and imaging tests have been emphasized for the clinical assessment of patients with CKD besides renal biopsy. The objective of the current study was to investigate whether osteoprotegerin (OPG) could be made a useful biomarker for early diagnosis of CKD-MBD.. Sixty pre-dialysis patients with CKD 1-5 were enrolled in this study. The serum calcium, phosphorus, blood urea nitrogen, creatinine, alkaline phosphatase, Osteocalcin, Calcitonin, intact parathyroid hormone and OPG were measured. Bone mineral densities of the lumbar spine (L2-L4), femoral neck, Ward's triangle and trochanter were measured by dual-energy X-ray absorptiometry.. Among all measured serum bone metabolism indexes, the changing of serum OPG level happened at the earliest time (CKD 3) and its correlation coefficient with estimated glomerular filtration rate (eGFR) was also the highest (r = -0.601, P = 0.001). In the multivariable analysis that included sex, age and eGFR as controlling factors, the serum OPG correlated with the bone mineral density (BMD) of Ward's triangle (r = -0.390, P = 0.041).. Serum OPG may be a useful biomarker for early diagnosis of CKD-MBD.

Topics: Absorptiometry, Photon; Adult; Analysis of Variance; Biomarkers; Bone Density; China; Chronic Disease; Chronic Kidney Disease-Mineral and Bone Disorder; Early Diagnosis; Female; Femur; Femur Neck; Glomerular Filtration Rate; Humans; Kidney Diseases; Lumbar Vertebrae; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Risk Assessment; Risk Factors; Severity of Illness Index

Osteoprotegerin (OPG), a cytokine that regulates bone resorption, has been implicated in the process of vascular calcification and stiffness.. Serum OPG was measured in 351 participants with chronic kidney disease (CKD) from one site of the Chronic Renal Insufficiency Cohort Study. Cortical bone mineral content (BMC) was measured by quantitative computed tomography in the tibia. Multivariable linear regression was used to test the association between serum OPG and traditional cardiovascular risk factors, measures of abnormal bone and mineral metabolism, and pulse wave velocity.. Higher serum OPG levels were associated with older age, female gender, greater systolic BP, lower estimated GFR, and lower serum albumin. OPG was not associated with measures of abnormal bone or mineral metabolism including serum phosphorus, albumin-corrected serum calcium, intact parathyroid hormone, bone-specific alkaline phosphatase, or cortical BMC. Among 226 participants with concurrent aortic pulse wave velocity measurements, increasing tertiles of serum OPG were associated with higher aortic pulse wave velocity after adjustment for demographics, traditional vascular risk factors, and nontraditional risk factors such as estimated GFR, albuminuria, serum phosphate, corrected serum calcium, presence of secondary hyperparathyroidism, serum albumin, and C-reactive protein or after additional adjustment for cortical BMC in a subset (n = 161).. These data support a strong relationship between serum OPG and arterial stiffness independent of many potential confounders including traditional cardiovascular risk factors, abnormal bone and mineral metabolism, and inflammation.

Topics: Aged; Analysis of Variance; Aorta; Biomarkers; Bone Density; Cardiovascular Diseases; Chi-Square Distribution; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Female; Humans; Kidney Diseases; Linear Models; Male; Middle Aged; Osteoprotegerin; Pulsatile Flow; Regional Blood Flow; Risk Assessment; Risk Factors; Tibia; Tomography, X-Ray Computed; United States; Up-Regulation

Vascular calcifications (VCs) are important predictors of cardiovascular mortality in patients with chronic kidney disease (CKD). We have shown previously that osteoprotegerin (OPG), a potential early biomarker for VC, was an independent predictor of mortality in CKD patients. The aim of our study was to follow longitudinally coronary and aortic VCs. VCs were measured using Siemens 16 detector CT in a group of predialysis and hemodialyzed patients before and after a follow-up of 4 years. Some of these patients were transplanted in the meantime. Renal function, calcium, phosphate, iPTH, hs-CRP (high sensitive protein C reactive), and OPG serum levels were also compared. VCs progressed in predialysis, hemodialyzed, and transplanted patients but the progression was not the same in all arterial beds. A progression of coronary calcifications was observed in predialysis and transplanted patients, while aortic calcifications worsened significantly only in hemodialyzed patients. OPG serum levels and hs-CRP were significantly lower among transplanted patients. We concluded that VC depends on the severity of the kidney disease. Transplanted patients are not protected from VC, yet their OPG serum levels were significantly lower, suggesting that there is no link between between OPG levels and severity of VC. Longer follow-up of these patients would be necessary to assess whether a decline in OPG correlates with better survival.

Topics: Adult; Aged; Aortic Diseases; Belgium; Biomarkers; Calcinosis; Coronary Artery Disease; Female; Humans; Kidney Diseases; Kidney Transplantation; Least-Squares Analysis; Linear Models; Longitudinal Studies; Male; Middle Aged; Osteoprotegerin; Prognosis; Renal Dialysis; Severity of Illness Index; Time Factors; Tomography, X-Ray Computed

Cardiovascular disease is the leading cause of death in the chronic kidney disease (CKD) population. The mechanisms of vascular damage are not fully understood. The objective of this study was to prospectively investigate the importance of novel mediators of vascular damage, in conjunction with vascular calcification (VC), on survival.. A total of 134 subjects [60 haemodialysis (HD), 28 peritoneal dialysis (PD) and 46 CKD stage 4] were studied. All survivors completed 40 months of follow-up. VC was measured using multi-slice spiral CT of the superficial femoral artery. Circulating osteoprotegerin (OPG), Fetuin-A and high sensitivity C-reactive protein (hs-CRP) were measured in addition to standard clinical biochemical analysis.. After a 40-month follow-up, 31 patients had died (27 men and 4 women). Of 31 subjects, 31 had evidence of significant VC. The majority of deaths were in the HD group (48%), 36% were PD subjects and 16% were CKD subjects. The outcome of interest was survival at the end of follow-up. Multivariate logistical regression analysis revealed male gender [OR 8.06 (1.34-48.450) P = 0.02], OPG >25 pmol/L [OR 5.31(1.35-20.88) P = 0.02] and hypoalbuminaemia [OR 0.26 (0.12-0.56) P < 0.01], were associated with increased odds of death.. We have previously reported that VC and low albumin predict death in CKD stages 4 and 5 over a 2-year follow-up period. These data show that OPG, independent of CRP, is also associated with a negative outcome. The mechanisms remain to be elucidated; however, it is likely that they are associated with vascular damage through mechanisms in addition to VC.

Topics: C-Reactive Protein; Calcinosis; Cause of Death; Chronic Disease; Female; Humans; Kidney Diseases; Male; Middle Aged; Osteoprotegerin; Prospective Studies; Severity of Illness Index; Survival Rate; Time Factors; Vascular Diseases

Expression of bone proteins resulting from transdifferentiation of vascular smooth muscle cells into osteoblasts suggests that vascular calcifications are a bioactive process. Osteoprotegerin (OPG) could play a key role in bone-vascular calcification imbalance and could be a marker of vascular calcification extent and progression. The purpose of this study was to evaluate relationships between vascular risk biomarkers (including classic risk factors and OPG) and coronary artery calcification (CAC) extent in chronic kidney disease (CKD) patients and to establish within the markers the appropriate cut-off value to predict CAC.. A total of 133 non-dialyzed CKD patients at various stages of kidney disease [75 males/58 females, median age: 69.9 (27.4-94.6)] were enrolled, excluding extrarenal replacement therapy patients. All underwent chest multidetector computed tomography for CAC scoring. Blood samples were collected for measurement of vascular risk markers (kidney disease, inflammation, nutrition, calcium phosphate and OPG). A potential relationship between CAC and these biological markers was investigated, and a receiver-operating characteristic (ROC) curve was designed thereafter to identify a cut-off value of involved markers that best predicted the presence of CAC.. After adjustment for age, diabetes, smoking and gender, among biological markers, only low-estimated glomerular filtration rate using Modification of Diet in Renal Disease [OR = 3.63 (1.10-12.02)], high FEPO(4) [OR = 3.99 (1.17-13.6)] and high OPG levels [OR = 8.54 (2.14-34.11)] were associated with the presence of CAC. A protective effect of 1.25(OH)(2) vitamin D [OR = 0.20 (0.05-0.79)] and LDL cholesterol [OR = 0.27 (0.08-0.94)] on CAC was also observed. ROC curve analysis showed that the OPG best cut-off value predicting CAC was 757.7 pg/mL.. These results suggest that a CAC increase is strongly associated with a plasma OPG increase in CKD patients. The values of OPG >757.7 pg/mL allow us to predict the presence of CAC in these patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Calcinosis; Chronic Disease; Coronary Artery Disease; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Risk Factors; ROC Curve

Cardiovascular disease is the major cause of morbidity and mortality in chronic kidney disease (CKD) and early biomarkers are required which can predict disease and death in such patients. The aim of our study was to investigate if osteoprotegerin (OPG) could be a predictor of coronary artery calcification (CAC) and mortality in CKD.. A total of 77 outpatients (32 with pre-dialysis CKD and 45 undergoing hemodialysis) were followed-up during 2 years. Measurements of CAC were performed using Siemens Multidetector CT software and calcium scores were measured according to the Agatston method.. OPG was an independent predictor of the Agatston score for CAC and correlated with the degree of CAC in pre-dialysis patients. A two-sample t-test characterized survivors as having a better glomerular filtration rate, lower Agatston scores, and lower serum levels of OPG. Kaplan-Meier survival curves separated survivors from non-survivors at plasma OPG cut-off levels of <3.1 ng/mL. A multivariable logistic regression analysis showed that OPG was an independent predictor of mortality from all causes in CKD patients.. OPG predicted mortality in CKD patients and could be a valuable biomarker in early detection of CAC in these patients.

Topics: Adult; Aged; Biomarkers; Chronic Disease; Coronary Artery Disease; Female; Humans; Kidney Diseases; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Risk Factors; Survival Rate

The bone alkaline phosphatase (BALP) B1x isoform has previously only been identified in some adults with chronic kidney disease on dialysis and in human bone tissue. Twenty-nine patients, 3-20 years of age, with reduced renal function due to a variety of kidney diseases were examined. We measured parathyroid hormone (PTH), biointact (whole 1-84) PTH, osteoprotegerin (OPG), CrossLaps (CTX), tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) type I procollagen intact amino-terminal propeptide (PINP), osteocalcin, total alkaline phosphatase (ALP), and BALP isoforms B/I, B1x, B1, and B2. Fifty percent higher levels were detected of PTH vs. biointact PTH, demonstrating non-(1-84) PTH fragments detected by the PTH assay. Increased activities were found in five, four, and three patients for total ALP, B1, and B2, respectively. Sixteen (55%) patients had increased B/I levels. B1x was identified in two (7%) patients, who had OPG levels in the higher range independently of age, glomerular filtration rate (GFR), and biointact PTH. B1x was identified prior to and after 9 days of growth hormone (GH) therapy in one patient but not after 1, 3, 6, and 12 months, however. In conclusion, our study demonstrates that the novel BALP B1x isoform is occasionally found to be present in children with kidney disease but to a lesser degree in comparison with adults with chronic kidney disease on dialysis. It is essential to perform bone histomorphometry for future investigations in order to elucidate the exact nature of circulating B1x in patients with kidney disease for accurate classification of type of renal bone disease.

Topics: Adolescent; Adult; Alkaline Phosphatase; Biomarkers; Bone and Bones; Child; Child, Preschool; Cohort Studies; Female; Humans; Kidney Diseases; Male; Osteoprotegerin; Parathyroid Hormone; Protein Isoforms

The majority of patients with chronic kidney disease (CKD) have excessive vascular calcification; however, most studies demonstrate that a subset of CKD patients do not have, nor develop, vascular calcification despite similar exposure to the uremic environment. This suggests protective mechanisms, or naturally occurring inhibitors, of calcification may be important.. In order to determine the role of three inhibitors, fetuin-A, matrix gla protein (MGP), and osteoprotegerin (OPG) in the vascular calcification observed in patients with CKD-5, we (1) measured serum levels of these inhibitors and compared the levels to calcification assessed by computed tomography (CT); (2) examined arteries from CKD-5 patients by immunostaining for these inhibitors; and (3) examined the expression and effect of these inhibitors in cultured bovine vascular smooth muscle cells (BVSMCs) incubated in serum pooled from uremic patients compared to healthy controls.. There was a negative correlation of coronary artery calcification scores with serum fetuin-A levels (r=-0.30, P= 0.034) and a positive association with OPG levels (r= 0.29, P= 0.045). There was increasing immunostaining for both fetuin-A and MGP in arteries with increasing calcification graded semiquantitatively (P < 0.003). In vitro, fetuin-A added to mineralizing BVSMCs inhibited mineralization (P < 0.001). Compared to normal serum, BVSMCs incubated with uremic serum had a progressive increase in MGP expression with mineralization (P < 0.001) and increased expression of OPG in BVSMCs (P < 0.04).. These data demonstrate that fetuin-A, OPG, and MGP play an important role in the pathogenesis of uremic vascular calcification.

Topics: alpha-2-HS-Glycoprotein; Animals; Blood Proteins; Calcinosis; Calcium-Binding Proteins; Cattle; Cells, Cultured; Chronic Disease; Extracellular Matrix Proteins; Glycoproteins; Humans; Kidney Diseases; Matrix Gla Protein; Muscle, Smooth, Vascular; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases

Osteoporosis is a well known side-effect of long-term treatment with glucocorticoids. However, the precise mechanism of this disorder is unclear. Recently, osteoprotegerin (OPG) [osteoclastogenesis inhibitory factor (OCIF)] has been identified as a novel cytokine, which inhibits differentiation and activation of osteoclast. In the present study, in order to clarify the roles of OPG in the development of glucocorticoid-induced osteoporosis, we measured circulating OPG before and after glucocorticoid therapy.. The study subjects were 12 patients (five males, seven females, 53.4 +/- 4.8 [SE] years) with various renal diseases that required glucocorticoid therapy. All patients received glucocorticoids for the first time. Treatment was initiated at an average dose of 32.5 +/- 3.0 mg per day. Serum OPG was measured using enzyme-linked immunosorbent assay (ELISA). Laboratory data, markers of bone metabolism and circulating OPG were compared before and after treatment for 4 weeks.. Serum OPG prior to glucocorticoid therapy was positively and independently correlated with serum creatinine. Serum OPG decreased significantly (P: < 0.0001) from 1.03 +/- 0.14 to 0.77 +/- 0.12 ng/ml after short-term administration of glucocorticoids. Furthermore, serum osteocalcin as a marker of bone formation was also reduced markedly (P: = 0.001). On the other hand, there were no remarkable changes in serum calcium, total alkaline phosphatases, creatinine and intact parathyroid hormone in response to glucocorticoid administration.. These findings indicate that short-term administration of glucocorticoids significantly suppresses serum OPG and osteocalcin. It might participate in the development of glucocorticoid-induced osteoporosis via an enhancement of bone resorption and suppression of bone formation.

Topics: Female; Glucocorticoids; Glycoproteins; Humans; Kidney Diseases; Male; Middle Aged; Osteocalcin; Osteoporosis; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor