osteoprotegerin and Renal-Insufficiency

In the recent past, it has become increasingly clear that extracellular calcium and phosphate homeostasis is a tightly regulated process. Since the physiological serum concentrations of calcium and phosphate are several orders of magnitude above their solubility product, mechanisms inhibiting precipitation must be operative to prevent extraosseous calcification. A number of local and systemic calcification inhibitors, including fetuin-A, matrix Gla protein, and osteoprotegerin, have been identified in recent years. Deficiency and dysregulation of such factors may contribute to morbidity and even mortality. Extraosseous calcifications occur with high prevalence in patients with end-stage renal disease. In particular, vascular manifestations are clearly associated with cardiovascular events and decreased survival. In addition to the well-established roles of hyperphosphatemia and an increased calcium x phosphate product, the biological and potential clinical roles of disturbances in calcification inhibition in uremia are discussed in this overview.

Topics: alpha-2-HS-Glycoprotein; Blood Proteins; Calcinosis; Calcium-Binding Proteins; Child; Extracellular Matrix Proteins; Humans; Inflammation; Matrix Gla Protein; Osteoprotegerin; Receptors, Tumor Necrosis Factor; Renal Insufficiency

This review focuses on the impact of a recent breakthrough in bone cell biology for understanding the pathophysiology of bone/vascular abnormalities associated with uraemia.. Osteoprotegerin is a humoral osteoclastogenesis/osteoclast activation inhibitory factor, which belongs to the TNF-alpha receptor superfamily. Serum osteoprotegerin levels are elevated along with the deterioration of the glomerular filtration rate. The circulating osteoprotegerin molecules were likely to preserve the activity of osteoclastogenesis inhibition, and the levels in many dialysis patients were high enough to inhibit osteoclastogenesis. The higher serum osteoprotegerin levels were related to the development of vascular calcification.. Osteoprotegerin is a potential uraemic toxin that increases the skeletal resistance to PTH. However, the roles of increased circulating osteoprotegerin on bone and/or vascular abnormalities in uraemia remain to be clarified.

Topics: Bone and Bones; Bone Density; Bone Diseases; Glycoproteins; Humans; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Insufficiency; Uremia; Vascular Diseases

Data on the predictive role of estimated glomerular filtration rate (eGFR) and osteoprotegerin (OPG) for cardiovascular (CVD) and all-cause mortality risk have been presented by our group and others. We now present data on the interactions between OPG with stage I to III chronic kidney disease (CKD) for all-cause and CVD mortality.. The setting was a 15-year study of 1,292 women over 70 years of age initially randomized to a 5-year controlled trial of 1.2 g of calcium daily. Serum OPG and creatinine levels with complete mortality records obtained from the Western Australian Data Linkage System were available. Interactions were detected between OPG levels and eGFR for both CVD and all-cause mortality (P < 0.05). Compared to participants with eGFR ≥60 ml/min/1.73 m2 and low OPG, participants with eGFR of <60 ml/min/1.73 m2 and elevated OPG had a 61% and 75% increased risk of all-cause and CVD mortality respectively (multivariate-adjusted HR, 1.61; 95% CI, 1.27-2.05; P < 0.001 and HR, 1.75; 95% CI, 1.22-2.55; P = 0.003). This relationship with mortality was independent of decline in renal function (P<0.05). Specific causes of death in individuals with elevated OPG and stage III CKD highlighted an excess of coronary heart disease, renal failure and chronic obstructive pulmonary disease deaths (P < 0.05).. The association between elevated OPG levels with CVD and all-cause mortality was more evident in elderly women with poorer renal function. Assessment of OPG in the context of renal function may be important in studies investigating its relationship with all-cause and CVD mortality.

Topics: Aged; Australia; Biomarkers; Cardiovascular Diseases; Cardiovascular System; Creatinine; Female; Glomerular Filtration Rate; Humans; Osteoprotegerin; Prospective Studies; Renal Insufficiency; Renal Insufficiency, Chronic; Risk Factors

The high prevalence of cardiovascular morbidity and mortality among patients with chronic kidney disease (CKD) is observed especially in those undergoing dialysis. Osteoprotegerin (OPG) and its ligands, receptor activator of nuclear factor kappa-B ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have been associated with cardiovascular complications. Our aim was to study their role as cardiovascular risk factors in stage 5 CKD patients.. OPG, RANKL and TRAIL concentrations were measured in 69 hemodialyzed CKD patients and 35 healthy volunteers. In CKD patients, cardiovascular dysfunction was assessed with aortic pulse wave velocity (AoPWV), carotid artery intima-media thickness (CCA-IMT), coronary artery calcium score (CACS) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) serum concentrations. Cardiovascular and overall mortality data were collected during a 7-years follow-up.. OPG plasma concentrations were higher in CKD patients comparing to controls. Total soluble RANKL was lower and OPG/RANKL ratio higher in patients. Soluble TRAIL concentrations did not differ between the groups and OPG/TRAIL ratio was higher in CKD patients. OPG and OPG/TRAIL positively predicted long-term mortality (all-cause and cardiovascular) in CKD patients. OPG positively correlated with AoPWV, CCA-IMT and NT-proBNP whereas OPG/TRAIL with AoPWV and NT-proBNP. Described relationships were independent of classical and non-classical cardiovascular risk factors, with exception of age.. Our study confirmed the role of OPG as a biomarker of cardiovascular dysfunction and a predictor of mortality in stage 5 CKD. OPG/TRAIL ratio can be proposed as a predictor of cardiovascular dysfunction and mortality.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Case-Control Studies; Female; Humans; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Natriuretic Peptide, Brain; Osteoprotegerin; Proportional Hazards Models; RANK Ligand; Renal Insufficiency; Solubility; TNF-Related Apoptosis-Inducing Ligand

This study aims to evaluate BMD and bone biomarkers and to investigate the effects of immunosuppressives on bone disease after RTx. Thirty-three RTR aged 16.7 ± 3.7 yr and healthy controls (n = 32) were enrolled. There was no difference between pre-RTx BMD and BMD at the time of study (45.9 ± 30.9 months after RTx), while both values were lower than controls (p < 0.01 and p < 0.05, respectively). Worst BMD scores were obtained at sixth month after RTx (-0.2 ± 0.9) and best at fourth year (1.4 ± 1.3). 25-hydroxy-(OH) vitamin D and OPG were higher in RTR (p < 0.001). BMD z scores negatively correlated with OPG and cumulative CS doses at the time of study (r = -0.344, p < 0.05 and r = -0.371, p < 0.05, respectively). Regression analysis revealed OPG as the only predictor of BMD (β -0.78, 95% CI -0.004 to -0.013, p < 0.001). The increase in OPG, a significant predictor of BMD, could either be secondary to graft dysfunction or for protection against bone loss. CS doses should be minimized to avoid their untoward effects on bone metabolism.

Topics: Adolescent; Anthropometry; Biomarkers; Bone and Bones; Bone Density; Case-Control Studies; Child; Child, Preschool; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Osteoprotegerin; Parathyroid Hormone; RANK Ligand; Renal Insufficiency; Vitamin D; Young Adult

Elevated osteoprotegerin (OPG) levels are inversely correlated with creatinine clearance and end-stage renal disease in patients with diabetes, however its role in predicting decline in renal function and progression to a more advanced stage disease in the elderly general population is unknown.. This was a prospective cohort study of 1,157 elderly women with serum OPG measured in 1998 and renal function estimated using serum creatinine and cystatin C-based estimated glomerular filtration rate (eGFR) at 5-yearly intervals. The primary objective of the study was to determine the relationship of circulating OPG levels with 5- and 10-year renal decline.. At baseline, participants with elevated OPG above the median (≥2.2 ng/ml) had a 5.0% lower CKD-EPI-creatinine and cystatin C eGFR compared to participants with lower OPG levels. In multivariable-adjusted linear regression models, elevated OPG levels at baseline were associated with greater 5- and 10-year decline in CKD-EPI-creatinine and cystatin C eGFR (-0.105, p = 0.002 and -0.104, p = 0.010, respectively). Elevated OPG at baseline was associated with increased 5- and 10-year risk of rapid renal decline (OR 2.13, 95% CI 1.33-3.43, p = 0.002 and OR 4.10, 95% CI 1.49-11.27, p = 0.006, respectively) and renal disease hospitalizations or deaths (HR 1.99, 95% CI 1.31-3.03, p = 0.001) after adjusting for known risk factors.. Elevated OPG levels are associated with long-term renal dysfunction and may be provide a useful biomarker to predict the trajectory of renal decline in older women.

Topics: Aged; Biomarkers; Creatinine; Cystatin C; Disease Progression; Female; Glomerular Filtration Rate; Humans; Kidney; Longitudinal Studies; Multivariate Analysis; Osteoprotegerin; Proportional Hazards Models; Prospective Studies; Renal Insufficiency; Risk Factors

Fetuin-A and osteoprotegerin (OPG) are arterial calcification regulators, which are related to cardiovascular survival in hemodialysis patients. We hypothesized that a balance of these calcification regulators might mediate the progression of left ventricular (LV) diastolic dysfunction in hemodialysis patients. We recruited 63 hemodialysis patients and measured their serum fetuin-A, OPG, arterial stiffness, aortic calcification and echocardiographic parameters, including the transmitral early diastolic velocity/tissue Doppler mitral annular early diastolic velocity ratio (E/E'), and analyzed the relationships between these variables. Fetuin-A levels were significantly and negatively correlated with the ankle-brachial pulse wave velocity (baPWV), aortic calcification score (AOCS), left atrial volume index (LAVI), LV mass index (LVMI) and E/E'. OPG levels and the ratio of OPG to fetuin-A levels were significantly and positively correlated with the baPWV, AOCS, LAVI and E/E'. A stepwise multiple regression analysis revealed that E/E' was independently correlated with fetuin-A levels (β=-0.334, P=0.02), OPG levels (β=0.367, P=0.01) and the ratio of OPG to fetuin-A (β=0.295, P=0.04). Categorizing the patients according to their serum fetuin-A and OPG levels revealed that patients with low fetuin-A and high OPG levels had the highest LAVI, LVMI and E/E' values after adjusting for potential confounders. Serum fetuin-A levels negatively reflected, whereas OPG levels and the ratio of OPG to fetuin-A positively reflected an increase in vascular and ventricular stiffness, leading to the aggravation of diastolic dysfunction. Therefore, based on our results, the balance of the tissue calcification regulators fetuin-A and OPG could mediate the progression of LV diastolic dysfunction in hemodialysis patients.

Topics: Aged; alpha-2-HS-Glycoprotein; Ankle Brachial Index; Blood Flow Velocity; Diastole; Female; Humans; Male; Middle Aged; Osteoprotegerin; Renal Dialysis; Renal Insufficiency; Ventricular Dysfunction, Left

Serum receptor activator of nuclear factor-κ B ligand and osteoprotegrin are mediated to vascular calcification in the general population. Our knowledge is very sparse in hemodialysis and renal transplant patients. Receptor activator of nuclear factor-κ B ligand, osteoprotegrin, intact parathyroid hormone, calcium, and phosphorus were measured in blood samples of 45 hemodialysis and 45 age-matched renal transplant patients. Osteoprotegrin (P = 0.001) and intact parathyroid hormone (P = 0.001) levels in the hemodialysis patients were higher than the renal transplant recipients. Osteoprotegrin had positive correlation with duration of dialysis and age in the hemodialysis (r = 0.88, P = 0.001 and r = 0.34, P = 0.02, respectively) and renal transplant patients (r = 0.92, P = 0.001 and r = 0.46, P = 0.001, respectively). Hemodialysis patients have higher osteoprotegrin levels than the renal transplant recipients. It may act as a protective factor for renal osteodystrophy or only as a secondary phenomenon of advanced renal failure.

Topics: Adult; Age Factors; Calcinosis; Calcium; Female; Humans; Kidney Transplantation; Male; Middle Aged; Osteoprotegerin; Parathyroid Hormone; Phosphorus; RANK Ligand; Renal Dialysis; Renal Insufficiency; Time Factors

Serum levels of OPG and RANKL and their clinical correlations were analyzed in 66 newly-diagnosed patients with multiple myeloma (MM). RANKL and RANKL /OPG ratio were significantly increased in advanced clinical stages and high grade myeloma bone disease (MBD), while OPG showed a tendency to decrease. Renal failure modified the expression of OPG. RANKL and RANKL/OPG ratios are informative markers for myeloma tumor burden and MBD.

Topics: Biomarkers; Bone Neoplasms; Humans; Multiple Myeloma; Osteoprotegerin; RANK Ligand; Renal Insufficiency; Tumor Burden

The aim of our work was to test the influence of L-carnitine supplementation on secondary hyperparathyroidism and bone metabolism in hemodialyzed patients in a randomized study. Eighty-three chronically hemodialyzed patients were observed; 44 were supplemented with L-carnitine (15 mg/kg intravenously after each hemodialysis for 6 months), while 39 took placebo. Levels of free carnitine (CAR), calcium (Ca), inorganic phosphate (P), Ca x P product, parathormone (PTH), bone-specific alkaline phosphatase (b-ALP), osteocalcin (OC), and osteoprotegerin (OPG) were monitored. In comparison with pretreatment values, changes of some selected parameters occurred in the supplemented patients after 6 months (data are expressed as medians; NS, nonsignificant change): PTH, 186.0 vs. 135.5 ng/L (NS); b-ALP, 13.9 vs. 13.2 microg/L (P < 0.05); OC, 78.3 vs. 68.8 microg/L (NS); OPG, 144.0 vs. 182.0 ng/L (P < 0.05). In the controls, there were the following changes: PTH, 148.0 vs. 207.0 ng/L (NS); b-ALP, 15.2 vs. 13.2 microg/L (P < 0.05); OC, 62.7 vs. 79.8 microg/L (P < 0.05); OPG, 140.0 vs. 164.0 ng/L (NS). A significant correlation was found between CAR and OPG changes (r = 0.51, P < 0.001) in the supplemented patients. The supplementation led to a significant increase of serum OPG concentration. Nevertheless, we observed only nonsignificant tendencies to correction of secondary hyperparathyroidism and reduction of bone turnover in hemodialyzed patients supplemented with L-carnitine in contrast to controls. At this point, the use of L-carnitine does not seem to be justified.

Topics: Aged; Bone and Bones; Bone Density; Calcium; Carnitine; Dietary Supplements; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Osteocalcin; Osteoporosis; Osteoprotegerin; Phosphates; Renal Dialysis; Renal Insufficiency; Treatment Outcome; Up-Regulation