Non-traditional risk factors predict coronary calcification in chronic kidney disease in a population-based cohort

Prognostic significance of peritoneal dialysis effluent mitochondrial DNA level

This editorial refers to ‘Osteopontin deficiency dampens the pro-atherogenic effect of uraemia’ by T.X. Pedersen et al. , pp. 352–359, this issue. The incidence of cardiovascular disease remains high in the population with renal failure and constitutes the leading cause of morbidity and mortality in these patients. According to the U.S. Renal Data System 2011 Annual Data Report, the rate of death among dialysis patients attributable to cardiovascular disease was 40% and 5% to acute myocardial infarction.1 However, the mechanisms by which renal failure accelerates development of vascular disease and magnifies cardiovascular morbidity and mortality remain elusive. As a common component in development of atherosclerosis, calcification characterizes vasculopathy, contributes to plaque rupture and thrombosis, and predicts high mortality in hemodialysis patients.2 In addition to traditional risk factors, this complication is associated with non-traditional factors such as elevated serum phosphorus and serum calcium × phosphorus product in uraemia.3 However, recent evidence suggests that the mechanism underpinning vascular calcification in uraemia is more than passive metastatic calcification, but an active cell-mediated process. Furthermore, osteopontin (OPN) has emerged as a key regulator in development of atherosclerosis-associated vasculopathy. OPN, a small integrin-binding ligand, N -linked (SIBLING) glycoprotein first identified in 1986 as …

Determinants of Coronary Calcium Conversion Among Patients With a Normal Coronary Calcium Scan: What Is the “Warranty Period” for Remaining Normal?

The striking improvement in cardiovascular therapies during the last several decades has caused a marked decrease in mortality linked to atherosclerotic diseases in Western societies. Nonetheless, coronary artery disease (CAD) remains the main cause of non-fatal events, and it is associated with substantial functional impairment in survivors of acute events, imposing a very large economic burden on societies. The use of risk scoring tools helps to identify patients both at higher risk of disease and those who are most likely to benefit from therapeutic intervention. Unfortunately, it has become apparent that most of these tools are not completely accurate, and many patients considered to be at low risk suffer coronary events, and, on the contrary, intermediate- to high-risk patients may actually be at a much lower risk than predicted. The attention of several investigators, therefore, turned to the development of imaging tools to identify atherosclerosis or its signature in its pre-clinical stages.

Insight is provided herein into the novel mechanisms of cardiometabolic risk. Previous reports, including the epidemiological work of the Turkish Adult Risk Factor study, indicated that proinflammatory state and oxidative stress are crucial for evaluating cardiometabolic risk. Autoimmune pathways in the course of oxidative stress are major determinants of cardiorenal and metabolic risk. The latter encompasses metabolic syndrome, type 2 diabetes, coronary heart disease, and chronic kidney disease (CKD). Along with platelet-activating factor acetylhydrolase, creatinine, thyroid stimulating hormone, acylation-stimulating protein, asymmetric dimethylarginine, and serum lipoprotein[Lp](a) are triggers of systemic low-grade inflammation and enhanced autoimmune reactions. Related studies are analyzed in the current review. Lp(a) plays a crucial role by taking part in the immune activation, thereby accelerating the course of diabetes, CKD, and other chronic disorders. Populations prone to impaired glucose tolerance, and particularly peri- and postmenopausal women, are at high risk of developing related vascular complications.

ObjectiveVascular calcification is a common pathobiological process which occurs among the elder population and in patients with diabetes and chronic kidney disease. Osteoprotegerin, a secreted glycoprotein that regulates bone mass, has recently emerged as an important regulator of the development of vascular calcification. However, the mechanism is not fully understood. The purpose of this study is to explore novel signaling mechanisms of osteoprotegerin in the osteoblastic differentiation in rat aortic vascular smooth muscle cells (VSMCs).Methods and ResultsVSMCs were isolated from thoracic aorta of Sprague Dawley rats. Osteoblastic differentiation of VSMCs was induced by an osteogenic medium. We confirmed by Von Kossa staining and direct cellular calcium measurement that mineralization was significantly increased in VSMCs cultured in osteogenic medium; consistent with an enhanced alkaline phosphatase activity. This osteoblastic differentiation in VSMCs was significantly reduced by the addition of osteoprotegerin in a dose responsive manner. Moreover, we identified, by real-time qPCR and western blotting, that expression of Notch1 and RBP-Jκ were significantly up-regulated in VSMCs cultured in osteogenic medium at both the mRNA and protein levels, these effects were dose-dependently abolished by the treatment of osteoprotegerin. Furthermore, we identified that Msx2, a downstream target of the Notch1/RBP-Jκ signaling, was markedly down-regulated by the treatment of osteoprotegerin.ConclusionOsteoprotegerin inhibits vascular calcification through the down regulation of the Notch1-RBP-Jκ signaling pathway.

As children with chronic kidney disease (CKD) have a long lifespan, optimal control of bone and mineral homeostasis is essential not only for the prevention of debilitating skeletal complications and for achieving adequate growth but also for preserving long-term cardiovascular health. As the growing skeleton is highly dynamic and at particular risk of deterioration, close control of bone and mineral homeostasis is required in children with CKD. However, assessment of bone disease is hampered by the limited validity of biochemical parameters-major controversy exists on key issues such as parathyroid hormone target ranges and the lack of useful imaging techniques. The role of newly discovered factors in bone and mineral homeostasis, such as fibroblast growth factor 23, is not yet established. Even though scientific evidence is limited in children with CKD, ergocalciferol or cholecalciferol supplementation and the use of calcium-free phosphate binders is recommended. The new drug cinacalcet is highly promising; however, pediatric experience is still limited to observational data and the effect of cinacalcet on longitudinal growth and pubertal development is unknown. Randomized, controlled trials are underway, including studies of cinacalcet pharmacokinetics and pharmacodynamics in infants.

Coronary artery calcification (CAC) and low bone density are coexisting deleterious conditions commonly shared by chronic kidney disease (CKD) patients. In the present study, we aimed to investigate whether the progression of CAC was associated with overtime reduction in bone density in non-dialyzed CKD patients. This is a prospective study of 24 months including 72 non-dialyzed CKD patients Stages 2 - 4 (age 57.6 ± 10.3 years, 62% male, 22% diabetics). CAC and vertebral bone density (VBD) were measured by computed tomography. At baseline, 46% of the patients had CAC (calcified group) and calcification was not identified in 54% of the patients (non-calcified group). The calcified group was older, predominantly male, and had lower VBD in comparison to non-calcified group. CAC progression was observed only in the calcified group (91% of the patients increased calcium score). The multiple regression analysis revealed loss of VBD as the independent determinant of CAC progression in these patients. CAC progression was associated with loss of VBD in non-dialyzed CKD patients.

Coronary artery calcification (CAC) is highly prevalent in dialysis-naive patients with chronic kidney disease (CKD). However, there are sparse data on the association of CAC with subsequent risk of cardiovascular disease and all-cause mortality in this population. To study the prospective association of CAC with risk of cardiovascular disease and all-cause mortality among dialysis-naive patients with CKD. The prospective Chronic Renal Insufficiency Cohort study recruited adults with an estimated glomerular filtration rate of 20 to 70 mL/min/1.73 m2 from 7 clinical centers in the United States. There were 1541 participants without cardiovascular disease at baseline who had CAC scores. Coronary artery calcification was assessed using electron-beam or multidetector computed tomography. Incidence of cardiovascular disease (including myocardial infarction, heart failure, and stroke) and all-cause mortality were reported every 6 months and confirmed by medical record adjudication. During an average follow-up of 5.9 years in 1541 participants aged 21 to 74 years, there were 188 cardiovascular disease events (60 cases of myocardial infarction, 120 heart failures, and 27 strokes; patients may have had >1 event) and 137 all-cause deaths. In Cox proportional hazards models adjusted for age, sex, race, clinical site, education level, physical activity, total cholesterol level, high-density lipoprotein cholesterol level, systolic blood pressure, use of antihypertensive treatment, current cigarette smoking, diabetes status, body mass index, C-reactive protein level, hemoglobin A1c level, phosphorus level, troponin T level, log N-terminal pro-B-type natriuretic peptide level, fibroblast growth factor 23 level, estimated glomerular filtration rate, and proteinuria, the hazard ratios associated with per 1 SD log of CAC were 1.40 (95% CI, 1.16-1.69; P < .001) for cardiovascular disease, 1.44 (95% CI, 1.02-2.02; P = .04) for myocardial infarction, 1.39 (95% CI, 1.10-1.76; P = .006) for heart failure, and 1.19 (95% CI, 0.94-1.51; P = .15) for all-cause mortality. In addition, inclusion of CAC score led to an increase in the C statistic of 0.02 (95% CI, 0-0.09; P < .001) for predicting cardiovascular disease over use of all the above-mentioned established and novel cardiovascular disease risk factors. Coronary artery calcification is independently and significantly related to the risks of cardiovascular disease, myocardial infarction, and heart failure in patients with CKD. In addition, CAC improves risk prediction for cardiovascular disease, myocardial infarction, and heart failure over use of established and novel cardiovascular disease risk factors among patients with CKD; however, the changes in the C statistic are small.

Malnutrition, inflammation, and atherosclerosis are significant problems in patients on hemodialysis. A prospective, observational study in 100 hemodialysis patients for 2 years was conducted. The primary outcomes were hospitalizations and mortality at the end of 2 years. The mean age was 61 ± 11.3 years and 69% were male. Seven patients did not complete the study (five underwent transplant and two were shifted to other units). Serum albumin was significantly lower in malnourished patients at 6 months from the beginning of the study period (3.58 vs. 3.79 g/dl, P = 0.001). Malnutrition based on subjective global assessment (SGA) was seen in 30 (32%) patients: mild to moderate in 27 (29%) and severe in 3 (3%). Inflammation was seen in 73 (78.5%) patients and intimal-medial thickness of >1.1 mm indicating significant atherosclerosis was seen in 73 (78.5%) patients. Modified SGA score and malnutrition-inflammation score (MIS) were significantly more in the malnourished group. Statistically significant association was seen between hospitalization and mortality in the malnourished population, and the odds ratio of death in malnourished patients was 9.83 (95% confidence interval: 2.8–34.3, P < 0.001). There was a moderate correlation between malnutrition assessed by modified SGA and MIS score (r = 0.54, P < 0.001). Mortality rate was 37% in patients with mild to moderate and 67% in severe malnutrition. Hospital admission was seen in 43 (46%) patients and was significantly more common in malnourished compared to well-nourished patients (77% vs. 32%, P < 0.001). Multiple logistic regression analysis showed that malnutrition by Modified SGA was the only significant variable associated with mortality at 2 years, and addition of MIS score did not improve the predictive ability of the model to modified SGA. We recommend the use of modified SGA and serial serum albumin to monitor nutrition in hemodialysis patients.