Comparison of the effects of lanthanum carbonate and calcium carbonate on the progression of cardiac valvular calcification after initiation of hemodialysis.

BACKGROUND: Although mineral metabolism disorder influences cardiac valvular calcification (CVC), few previous studies have examined the effects of non-calcium-containing and calcium-containing phosphate binders on CVC in maintenance hemodialysis patients. The aim of the present study was to compare the effects of lanthanum carbonate (LC) with calcium carbonate (CC) on the progression of CVC in patients who initiated maintenance hemodialysis and to investigate clinical factors related to CVC. METHODS: The current study included 50 subjects (mean age 65 years, 72% males) from our previous randomized controlled trial (LC group, N = 24; CC group, N = 26). CVC was evaluated as CVC score (CVCS) using echocardiography at baseline and 18 months after initiation of hemodialysis. We compared CVCS and the changes between the two groups. We also analyzed the associations between CVCS and any other clinical factors including arterial plaque score (PS) and serum phosphorus levels. RESULTS: Baseline characteristics of study participants including CVCS were almost comparable between the two groups. At 18 months, there were no significant differences in mineral metabolic markers or CVCS between the two groups, and CVCS were significantly correlated with PS (r = 0.39, p < 0.01). Furthermore, changes in CVCS were significantly correlated with average phosphorus levels (r = 0.36, p < 0.05), which were significantly higher in high serum phosphorus and high PS group compared to low serum phosphorus and low PS group (p < 0.05). CONCLUSIONS: In the present study, there were no significant differences between LC and CC with regard to progression of CVC. However, serum phosphorus levels and arterial plaque seem to be important for the progression and formation of CVC in hemodialysis patients.

A patient with extensive cerebral calcification due to pseudohypoparathyroidism: a case report.

BACKGROUND: Pseudohypoparathyroidism(PHP) is a heterogeneous group of disorders due to impaired activation of c AMP dependant pathways following binding of parathyroid hormone (PTH) to its receptor. In PHP end organ resistance to PTH results in hypocalcaemia, hyperphosphataemia and high PTH levels. CASE PRESENTATION: A 59 year old male presented with a history of progressive impairment of speech and unsteadiness of gait for 1 week and acute onset altered behavior for 1 day and one episode of generalized seizure. His muscle power was grade four according to MRC (medical research council) scale in all limbs and Chovstek's and Trousseau's signs were positive. Urgent non contrast computed tomography scan of the brain revealed extensive bilateral cerebral and cerebellar calcifications. A markedly low ionized calcium level of 0.5 mmol/l, an elevated phosphate level of 9.5 mg/dl (reference range: 2.7-4.5 mg/dl) and an elevated intact PTH of 76.3 pg/l were noted. His renal functions were normal. His hypocalcemia was accentuated by the presence of hypomagnesaemia. His 25 hydroxy vitamin D level was only marginally low which could not account for severe hypocalcaemia. A diagnosis of pseudohypoparathyroidism without phenotypic defects, was made due to hypocalcaemia and increased parathyroid hormone levels with cerebral calcifications. The patient was treated initially with parenteral calcium which was later converted to oral calcium supplements. His coexisting Vitamin D deficiency was corrected with 1αcholecalciferol escalating doses. His hypomagnesaemia was corrected with magnesium sulphate parenteral infusions initially and later with oral preparations. With treatment there was a significant clinical and biochemical response. CONCLUSION: Pseudohypoparathyroidism can present for the first time in elderly resulting in extensive cerebral calcifications. Identification and early correction of the deficit will result in both symptomatic and biochemical response.

Myocardial calcification in a patient with B-lymphoblastic leukemia accompanied by tumor lysis syndrome.

Myocardial calcification, a rare disease that leads to chronic or acute heart failure and with a poor prognosis, occurs in patients with abnormal calcium-phosphorus metabolism. The association between myocardial calcification and tumor lysis syndrome has not been reported to date. A 50-year-old man with hyperthermia and general malaise presented to our hospital and was clinically diagnosed with B-lymphoblastic leukemia (B-ALL) and febrile neutropenia accompanied by septic shock. Prednisolone was administered for tumor reduction. Two to three hours later, electrocardiography demonstrated ST elevation in V4-6, and blood tests showed elevated levels of cardiac enzymes. Transthoracic echocardiogram revealed diffuse severe hypokinesis with decreased left ventricular ejection fraction. Additionally, blood tests showed that serum phosphorus level increased to 8.0 mg/dl, which was likely due to tumor lysis syndrome. Circulatory and respiratory failure due to left heart failure progressed, and he died 3 days after administration of prednisolone. Pathological autopsy revealed diffuse proliferation of atypical B-lymphoblasts in the bone marrow, which led to the pathological diagnosis of B-ALL, accompanied by necrosis. On the cut surface of the heart, the left ventricle was dilated, and patchy yellowish-brown areas were present in the epicardial-side of the myocardium and spread through the circumferential wall of the left ventricle and interventricular septum. Microscopically, myocardial fibers were granularly basophilic in that area and were revealed as calcium deposits by Von Kossa staining. He was diagnosed with myocardial calcification. The drastic increase in the serum phosphorus level caused by tumor lysis syndrome seemed to be associated with myocardial calcification.

Acroosteolysis and bone metabolism parameters distinguish female patients with limited systemic sclerosis with and without calcinosis: a case control study.

Calcinosis usually represents a late manifestation of systemic sclerosis (SSc), inducing tissue damage and chronic calcifications. To analyze clinical and bone metabolism parameters associated with calcinosis in limited systemic sclerosis (lSSc), thirty-six female lSSc patients with calcinosis were compared with 36 female lSSc patients without calcinosis, matched by age, disease duration, and body mass index. Organ involvement, autoantibodies, bone density, and laboratory parameters were analyzed. Statistical significance was considered if p < 0.05. Calcinosis was significantly associated with acroosteolysis (69% vs. 22%, p < 0.001), higher modified Rodnan skin score (mRSS 4.28 ± 4.66 vs. 1.17 ± 2.50, p < 0.001), and higher 25-hydroxyvitamin D (25OHD) (24.46 ± 8.15 vs. 20.80 ± 6.60 ng/ml, p = 0.040) and phosphorus serum levels (3.81 ± 0.41 vs. 3.43 ± 0.45 mg/dl, p < 0.001). 25OHD levels > 30 ng/ml were also significantly more frequent in patients with calcinosis (p = 0.041). Regarding treatment, current use of corticosteroids was lower in patients with calcinosis compared with patients without calcinosis (8% vs. 28%, p = 0.032). On logistic regression analysis, acroosteolysis (OR = 12.04; 95% CI, 2.73-53.04; p = 0.001), mRSS (OR = 1.37; 95% CI, 1.11-1.69; p = 0.003), phosphorus serum levels (OR = 5.07; 95% CI, 1.06-24.23; p = 0.042), and lower glucocorticoid use (OR = 0.07; 95% CI, 0.007-0.66; p = 0.021) are independent risk factors for calcinosis. This study showed that limited SSc patients with calcinosis present a distinct clinic and biochemical profile when compared with a matched group without calcinosis, paired by disease duration, age and BMI. KEY POINTS: • Calcinosis in patients with limited SSc was associated with acroosteolysis, higher mRSS and higher serum levels of phosphorus.

Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome.

PURPOSE: Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development. METHODS: Children from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction. RESULTS: Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03). CONCLUSIONS: Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.

Oral Sodium Bicarbonate Supplementation Does Not Affect Serum Calcification Propensity in Patients with Chronic Kidney Disease and Chronic Metabolic Acidosis.

BACKGROUND: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD) and metabolic acidosis might accelerate vascular calcification. The T50 calcification inhibition test (T50-test) is a global functional test analyzing the overall propensity of calcification in serum, and low T50-time is associated with progressive aortic stiffening and with all-cause mortality in non-dialysis CKD, dialysis, and transplant patients. Low serum bicarbonate is associated with a short T50-time and alkali supplementation could be a simple modifier of calcification propensity. The aim of this study was to investigate the short-term effect of oral sodium bicarbonate supplementation on T50-time in CKD patients. MATERIAL AND METHODS: The SoBic-study is an ongoing randomized-controlled trial in CKD-G3 and G4 patients with chronic metabolic acidosis (serum HCO3- ≤21 mmol/L), in which patients are randomized to either achieve serum HCO3- levels of 24 ± 1 mmol/L (intervention group) or 20 ± 1 mmol/L (rescue group). The effect of bicarbonate treatment on T50-time was assessed. RESULTS: The study cohort consisted of 35 (14 female) patients aged 57 (±15) years, and 18 were randomized to the intervention group. The mean T50-time was 275 (± 64) min. After 4 weeks, the mean change of T50-time was 4 (±69) min in the intervention group and 18 min (±56) in the rescue group (ß = -25; 95% CI: -71 to 22; p = 0.298). Moreover, change of serum bicarbonate in individual patients was not associated with change in T50-time, analyzed by regression analysis. Change of serum phosphate had a significant impact on change of T50-time (ß = -145; 95% CI: -237 to -52). CONCLUSION: Oral sodium bicarbonate supplementation showed no effect on T50-time in acidotic CKD patients.

Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society.

Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) <50 nmol/L or 20 ng/mL) is common in Europe and the Middle East. It occurs in <20% of the population in Northern Europe, in 30-60% in Western, Southern and Eastern Europe and up to 80% in Middle East countries. Severe deficiency (serum 25(OH)D <30 nmol/L or 12 ng/mL) is found in >10% of Europeans. The European Calcified Tissue Society (ECTS) advises that the measurement of serum 25(OH)D be standardized, for example, by the Vitamin D Standardization Program. Risk groups include young children, adolescents, pregnant women, older people (especially the institutionalized) and non-Western immigrants. Consequences of vitamin D deficiency include mineralization defects and lower bone mineral density causing fractures. Extra-skeletal consequences may be muscle weakness, falls and acute respiratory infection, and are the subject of large ongoing clinical trials. The ECTS advises to improve vitamin D status by food fortification and the use of vitamin D supplements in risk groups. Fortification of foods by adding vitamin D to dairy products, bread and cereals can improve the vitamin D status of the whole population, but quality assurance monitoring is needed to prevent intoxication. Specific risk groups such as infants and children up to 3 years, pregnant women, older persons and non-Western immigrants should routinely receive vitamin D supplements. Future research should include genetic studies to better define individual vulnerability for vitamin D deficiency, and Mendelian randomization studies to address the effect of vitamin D deficiency on long-term non-skeletal outcomes such as cancer.

Paricalcitol supplementation during the first year after kidney transplantation does not affect calcification propensity score.

BACKGROUND: Cardiovascular complications are common in kidney transplant patients and calcification propensity of blood, measured as T50, is associated with cardiovascular outcomes. Paricalcitol supplementation affects calcium/phosphate homeostasis and may affect calcification propensity. To assess this hypothesis we measured T50 in kidney transplant recipients participating in a randomized study comparing paricalcitol versus no treatment during the first year after kidney transplantation. METHODS: Stored serum samples from 76 kidney transplant recipients (paricalcitol n = 37, no treatment n = 39) were analyzed. Analyses were performed at inclusion (8 weeks after transplantation) and repeated one year after transplantation. RESULTS: There were no statistically significant differences in T50 between the paricalcitol and placebo groups, neither at baseline (p = 0.56) nor at 1 year (p = 0.61). Also, there were no significant changes in T50 over time in either group or when pooling all data (p <  0.20). In multivariate regression analysis, out of 16 potentially relevant covariates, comprising clinical and biochemical parameters, only plasma PTH and T50 at baseline were significantly correlated to T50 after one year. (p <  0.03 and p < 0.01, respectively). CONCLUSIONS: Calcium propensity measured as T50 score remained unchanged with paricalcitol treatment in kidney transplant recipients, and was not changed over time during the study period of one year. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01694160 , registered 23 September 2012.

Serum magnesium, phosphorus, and calcium levels and subclinical calcific aortic valve disease: A population-based study.

BACKGROUND AND AIMS: Calcific aortic valve disease (CAVD) is the most common valve disease. Although micronutrients are known to contribute to cardiovascular disease, the relationship with CAVD remains poorly evaluated. We examined the association of serum levels of magnesium, phosphorus, and calcium with prevalence, incidence, and progression of aortic valve calcification (AVC). METHODS: We conducted a prospective study in a population-based sample of Japanese men aged 40-79 years without known cardiovascular disease and chronic kidney disease at baseline, and quantified AVC from serial computed tomographic images with the Agatston method. RESULTS: Of 938 participants at baseline (mean age, 63.7 ±â€¯9.9 years), AVC prevalence was observed in 173 (18.4%). Of 596 participants without baseline AVC at follow-up (median duration, 5.1 years), AVC incidence was observed in 138 (23.2%). After adjustment for demographics, behaviors and cardiovascular risk factors, relative risks (95% confidence intervals) in the highest versus lowest categories of serum magnesium, phosphorus, and calcium were 0.62 (0.44-0.86), 1.45 (1.02-2.04), and 1.43 (0.95-2.15), respectively, for AVC prevalence and 0.62 (0.42-0.92), 1.93 (1.28-2.91), and 1.09 (0.77-1.55), respectively, for AVC incidence. Their linear trends of serum magnesium and phosphorus were also all statistically significant. Of 131 participants with baseline AVC, there was no association of any serum micronutrients with AVC progression. CONCLUSIONS: Serum magnesium was inversely associated, while serum phosphorus was positively associated with AVC prevalence and incidence, suggesting that these serum micronutrients may be potential candidates for risk prediction or prevention of CAVD, and warranting further studies.

Association between advanced oxidation protein products (AOPP) and vascular calcification in uremic patients.

OBJECTIVE: To investigate the correlation between serum advanced oxidation protein products (AOPP) and vascular calcification in uremic patients. PATIENTS AND METHODS: The general data of included subjects were collected, and the serum AOPP, intact parathyroid hormone (iPTH), creatinine (Cre), Urea, calcium (Ca), phosphorus (P), total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterin (LDL-C), hemoglobin (Hb) and albumin (ALB) were detected. Coronary artery computed tomography (CT) scan was performed and the coronary arterial calcification score (CACS) was calculated; the whole abdomen CT scan was performed and abdominal aortic calcification index (AACI) was calculated. SPSS l9.0 software was used for data analysis. RESULTS: The coronary artery CT and detection of serum indexes showed that AOPP in positive coronary arterial calcification group was significantly increased compared with that in negative coronary arterial calcification group (59.14 ± 14.57 vs. 37.59 ± 5.31) µmol/L. The whole abdomen CT and detection of serum indexes showed that AOPP in positive abdominal aortic calcification group was significantly increased compared with that in negative abdominal aortic calcification group (60.32 ± 15.43 vs. 39.57 ± 6.25) µmol/L. AOPP in severe calcification group was significantly higher than negative group (70.72 ± 18.18 vs. 39.57 ± 6.25) µmol/L. There were no significant differences in AOPP between hypertension and non-hypertension groups, diabetic nephropathy and non-diabetic nephropathy groups. Correlation analysis showed that AOPP of uremic patients had a significantly positive correlation with logl0[CACS+1] and had a significantly positive correlation with inferior AACI. CONCLUSIONS: AOPP in positive coronary arterial calcification group and positive abdominal aortic calcification group was higher than that in negative group and AOPP in severe calcification group was significantly higher than that in negative group. AOPP of uremic patients has a significantly positive correlation with CACS and AACI.

Eicosapentaenoic acid prevents arterial calcification in klotho mutant mice.

BACKGROUND: The klotho gene was identified as an "aging-suppressor" gene that accelerates arterial calcification when disrupted. Serum and vascular klotho levels are reduced in patients with chronic kidney disease, and the reduced levels are associated with arterial calcification. Intake of eicosapentaenoic acid (EPA), an n-3 fatty acid, reduces the risk of fatal coronary artery disease. However, the effects of EPA on arterial calcification have not been fully elucidated. The aim of this study was to determine the effect of EPA on arterial calcification in klotho mutant mice. METHODS AND RESULTS: Four-week-old klotho mutant mice and wild-type (WT) mice were given a diet containing 5% EPA (EPA food, klotho and WT: n = 12, each) or not containing EPA (control food, klotho and WT: n = 12, each) for 4 weeks. Calcium volume scores of thoracic and abdominal aortas assessed by computed tomography were significantly elevated in klotho mice after 4 weeks of control food, but they were not elevated in klotho mice after EPA food or in WT mice. Serum levels of EPA and resolvin E1, an active metabolite of EPA, in EPA food-fed mice were significantly increased compared to those in control food-fed mice. An oxidative stress PCR array followed by quantitative PCR revealed that NADPH oxidase-4 (NOX4), an enzyme that generates superoxide, gene expression was up-regulated in arterial smooth muscle cells (SMCs) of klotho mice. Activity of NOX was also significantly higher in SMCs of klotho mice than in those of WT mice. EPA decreased expression levels of the NOX4 gene and NOX activity. GPR120, a receptor of n-3 fatty acids, gene knockdown by siRNA canceled effects of EPA on NOX4 gene expression and NOX activity in arterial SMCs of klotho mice. CONCLUSIONS: EPA prevents arterial calcification together with reduction of NOX gene expression and activity via GPR120 in klotho mutant mice.

Antinuclear Matrix Protein 2 Autoantibodies and Edema, Muscle Disease, and Malignancy Risk in Dermatomyositis Patients.

OBJECTIVE: Dermatomyositis (DM) patients typically present with proximal weakness and autoantibodies that are associated with distinct clinical phenotypes. We observed that DM patients with autoantibodies recognizing the nuclear matrix protein NXP-2 often presented with especially severe weakness. The aim of this study was to characterize the clinical features associated with anti-NXP-2 autoantibodies. METHODS: There were 235 DM patients who underwent testing for anti-NXP-2 autoantibodies. Patient characteristics, including muscle strength, were compared between those with and without these autoantibodies. The number of cancer cases observed in anti-NXP-2-positive subjects was compared with the number expected in the general population. RESULTS: Of the DM patients, 56 (23.8%) were anti-NXP-2-positive. There was no significant difference in the prevalence of proximal extremity weakness in patients with and without anti-NXP-2. In contrast, anti-NXP-2-positive patients had more prevalent weakness in the distal arms (35% versus 20%; P = 0.02), distal legs (25% versus 8%; P < 0.001), and neck (48% versus 23%; P < 0.001). Anti-NXP-2-positive subjects were also more likely to have dysphagia (62% versus 35%; P < 0.001), myalgia (46% versus 25%; P = 0.002), calcinosis (30% versus 17%; P = 0.02), and subcutaneous edema (36% versus 19%; P = 0.01) than anti-NXP-2-negative patients. Five anti-NXP-2-positive subjects (9%) had cancer-associated myositis, representing a 3.68-fold increased risk (95% confidence interval 1.2-8.6) compared to the expected prevalence in the general population. CONCLUSION: In DM, anti-NXP-2 autoantibodies are associated with subcutaneous edema, calcinosis, and a muscle phenotype characterized by myalgia, proximal and distal weakness, and dysphagia. As anti-NXP-2-positive patients have an increased risk of cancer, we suggest that they undergo comprehensive cancer screening.

Clinical, biochemical, and radiological characterization of the calcinosis in a cohort of Mexican patients with systemic sclerosis.

Calcinosis is a frequent complication of systemic sclerosis (SSc) that is usually located in extremities but may occur across the board. The aim of our study was to identify and quantify the distribution of calcinosis in a cohort of Mexican patients with SSc and its association with clinical features and autoantibodies. A cohort of patients with SSc (2013 ACR/EULAR criteria), classified in diffuse cutaneous (dcSSc) and limited cutaneous (lcSSc) (Le Roy criteria), was studied. For their analysis, patients were allocated into those with and without calcinosis (clinical and/or radiological). The evaluation included the modified Rodnan scale for skin and Medsger disease severity scale (DSS). Calcium, phosphorus, vitamin D, and parathyroid hormone (PTH) and antinuclear antibodies and extractable nuclear antigens were determined in serum. A total of 109 patients were included, 41 (37 %) with and 68 (63 %) without calcinosis. Calcinosis was more frequent in patients with dcSSc (55 vs 27 %). In total, we identified 354 sites with calcinosis and mean per patient of 12.0 ± 9.1; the most common sites affected were the hands (83 %), proximal upper extremity (27 %), and proximal lower extremity (22 %). Patients with calcinosis had a higher score of Rodnan scale, Mesdger DSS, and frequency of anti-nucleolar and anti-Scl-70 antibodies compared to those without calcinosis. Abnormal PTH elevation was found in 35 % of patients with calcinosis and 23 % without it. The prevalence of calcinosis is high in Mexican patients with SSc, especially in diffuse variety, and is associated with increased severity of disease.

Serum phosphorus is related to left ventricular remodeling independent of renal function in hospitalized patients with chronic kidney disease.

BACKGROUND: Increasing evidence indicated that phosphorus emerged as an important cardiovascular risk factor in patients with chronic kidney disease (CKD). The fact that serum phosphorus was closely linked to vascular and valvar calcification may account for one important reason. However, left ventricular remodeling may also serve as another potential mechanism of the cardiac toxicity of phosphorus. In the present study, we evaluated the association of serum phosphorus with left ventricular remodeling. METHODS: We investigated consecutive hospitalized patients with pre-dialysis CKD, who did not have symptomatic heart failure or take any phosphorus binder or calcitriol medications. Transthoracic echocardiography was applied to assess their left ventricular remodeling indices, both structural and functional. RESULTS: The 296 study subjects (mean age 56.4years) included 169 (57.1%) men, 203 (68.6%) hypertensive patients. In addition to gender, systolic blood pressure, and estimated glomerular filtration rate, serum phosphorus was an independent determinant of left ventricular mass index (LVMI, P=0.001). Similarly, serum phosphorus was also a determinant of left ventricular end diastolic dimension (P=0.0003), but not of relative wall thickness. In multivariate logistic analyses, serum phosphorus was significantly and independently associated with the prevalence of left ventricular hypertrophy (LVH, odds ratio [OR] 2.38 for each 1mmol/L increase, 95% CI 1.20-4.75, P=0.01). Moreover, the association was only confirmatory in eccentric LVH (OR 3.01, 95% CI 1.43-6.32, P=0.003) but not in concentric LVH (1.38, 95% CI, 0.54-3.49, P=0.50). CONCLUSION: Serum phosphorus was significantly and independently associated with LVMI and the prevalence of eccentric LVH in hospitalized patients with CKD.

Nicotinamide treatment in a murine model of familial tumoral calcinosis reduces serum Fgf23 and raises heart calcium.

Mutations in the GALNT3 gene result in familial tumoral calcinosis, characterized by persistent hyperphosphatemia and ectopic calcific masses in soft tissues. Since calcific masses often recur after surgical removal, a more permanent solution to the problem is required. Nicotinamide is reported to lower serum phosphate by decreasing sodium-dependent phosphate co-transporters in the gut and kidney. However, its effectiveness in tumoral calcinosis remains unknown. In this study, we investigated nicotinamide as a potential therapy for tumoral calcinosis, using a murine model of the disease-Galnt3 knockout mice. Initially, five different doses of nicotinamide were given to normal heterozygous mice intraperitoneally or orally. Treatment had no effect on serum phosphate levels, but serum levels of a phosphaturic hormone, fibroblast growth factor 23 (Fgf23), decreased in a dose-dependent manner. Subsequently, high-dose nicotinamide (40mM) was tested in Galnt3 knockout mice fed a high phosphate diet. The radiographic data pre- and post-treatment showed that nicotinamide did not reverse the calcification. However, the treatment retarded calcification growth after 4weeks, while in the untreated animals, calcifications increased in size. The therapy did not affect serum phosphate levels, but intact Fgf23 decreased in the treated mice. The treated mice also had increased calcium in the heart. In summary, nicotinamide did not alter serum phosphate levels, likely due to compensatory decrease in Fgf23 to counteract the phosphate lowering effect of nicotinamide. Although increased calcium accumulation in the heart is a concern, the therapy appears to slow down the progression of ectopic calcifications.

Association of serum phosphorus variability with coronary artery calcification among hemodialysis patients.

Coronary artery calcification (CAC) is associated with increased mortality in patients on maintenance hemodialysis (MHD), but the pathogenesis of this condition is not well understood. We evaluated the relationship of CAC score (CACs) and variability in serum phosphorus in MHD patients. Seventy-seven adults on MHD at Huashan Hospital (Shanghai) were enrolled in July, 2010. CAC of all the patients were measured by computed tomography and CACs was calculated by the Agatston method at the entry of enrollment. Patients were divided into three categories according to their CACs (0∼10, 11∼400, and >400). Blood chemistry was recorded every 3 months from January 2008 to July 2010. Phosphorus variation was defined by the standard deviation (SD) or coefficient of variation (CV) and it was calculated from the past records. The ordinal multivariate logistic regression analysis was used to analyze the predictors of CAC. The mean patient age (± SD) was 61.7 years (±11.3) and 51% of patients were men. The mean CACs was 609.6 (±1062.9), the median CACs was 168.5, and 78% of patients had CACs more than 0. Multivariate analysis indicated that female gender (OR = 0.20, 95% CI = 0.07-0.55), age (OR = 2.31, 95% CI = 1.32-4.04), serum fibroblast growth factor 23 (OR = 2.25, 95% CI = 1.31-3.85), SD-phosphorus calculated from the most recent 6 measurements (OR = 2.12; 95% CI = 1.23-3.63), and CV-phosphorus calculated from the most recent 6 measurements (OR = 1.90, 95% CI = 1.16-3.11) were significantly and independently associated with CACs. These associations persisted for phosphorus variation calculated from past 7, 8, 9, 10, and 11 follow-up values. Variability of serum phosphorus may contribute significantly to CAC and keeping serum phosphorus stable may decrease coronary calcification and associated morbidity and mortality in MHD patients.

Predicting risk of coronary events and all-cause mortality: role of B-type natriuretic peptide above traditional risk factors and coronary artery calcium scoring in the general population: the Heinz Nixdorf Recall Study.

AIMS: Several biomarkers including B-type natriuretic peptide (BNP) have been suggested to improve prediction of coronary events and all-cause mortality. Moreover, coronary artery calcium (CAC) as marker of subclinical atherosclerosis is a strong predictor for cardiovascular mortality and morbidity. We aimed to evaluate the predictive ability of BNP and CAC for all-cause mortality and coronary events above traditional cardiovascular risk factors (TRF) in the general population. METHODS: We followed 3782 participants of the population-based Heinz Nixdorf Recall cohort study without coronary artery disease at baseline for 7.3 ± 1.3 years. Associations of BNP and CAC with incident coronary events and all-cause mortality were assessed using Cox regression, Harrell's c, and time-dependent integrated discrimination improvement (IDI(t), increase in explained variance). RESULTS: Subjects with high BNP levels had increased frequency of coronary events and death (coronary events/mortality: 14.1/28.2% for BNP ≥100 pg/ml vs. 2.7/5.5% for BNP < 100 pg/ml, respectively). Subjects with a BNP ≥100 pg/ml had increased incidence of hard endpoints sustaining adjustment for CAC and TRF (for coronary events: hazard ratio (HR) (95% confidence interval (CI)) 3.41(1.78-6.53); for all-cause mortality: HR 3.35(2.15-5.23)). Adding BNP to TRF and CAC increased measures of predictive ability: coronary events (Harrell's c, for coronary events, 0.775-0.784, p = 0.09; for all-cause mortality 0.733-0.740, p = 0.04; and IDI(t) (95% CI), for coronary events: 2.79% (0.33-5.65%) and for all-cause mortality 1.78% (0.73-3.10%). CONCLUSIONS: Elevated levels of BNP are associated with excess incident coronary events and all-cause mortality rates, with BNP and CAC significantly and complementary improving prediction of risk in the general population above TRF.

High serum phosphorus and FGF 23 levels are associated with progression of coronary calcifications.

BACKGROUND: Coronary calcifications (CC) portend increased mortality in adults receiving hemodialysis (HD), however the risk factors associated with CC progression are not well known in pediatric patients. Our previous cross-sectional studies demonstrated high CC prevalence (31 %) in pediatric patients, which were significantly associated with high serum phosphorus (P), fibroblast growth factor 23 (FGF) levels, dialysis vintage, and low cholesterol. The current study was undertaken to determine and elucidate CC progression in pediatric HD patients. METHODS: A 1-year prospective longitudinal study of 16 pediatric patients (ten male; mean age, 16.9 ± 3 years; range, 10.1-20.4 years) receiving chronic HD was conducted. RESULTS: CC were observed in five of 16 (31.3 %) patients on baseline computed tomogram (CT) scan; 14/16 patients underwent 1-year CT. All patients with initial CC who completed CT at 1 year (3/5) progressed; one patient had new CC and none of the patients had resolved CC. Mean Agatston score increased from 23.4 ± 18.06 HU (baseline) to 169 ± 298.9 HU. Patients with CC progression had higher mean serum P (8.6 ± 1.8 mg/dl vs. 6.3 ± 1.1 mg/dl, p = 0.015) and FGF 23 levels (3,994 ± 860.5 pg/ml vs. 2,327 ± 1,206.4 pg/ml, p = 0.028). Serum P and FGF 23 levels were positively correlated with final Agatston scores (R = 0.65, p = 0.01 for serum P and R = 0.54, p = 0.045 for FGF 23) and change in Agatston scores (R = 0.65, p = 0.01 for serum P and R = 0.52, p = 0.048 for FGF 23). CONCLUSIONS: Our study shows that CC is progressive in pediatric patients receiving HD and that increased serum P and FGF 23 levels are associated with this progression.

High phosphate feeding induced arterial medial calcification in uremic rats: roles of Lanthanum carbonate on protecting vasculature.

AIMS: High cardiovascular mortality in patients with end-stage renal disease is closely associated with arterial medial calcification (AMC) caused by hyperphosphatemia, the mechanism of which associated hormones (FGF-23, klotho) and osteochondrogenic events is unclear. We examined the effect of Lanthanum carbonate on AMC via regulating the abnormalities in phosphorus metabolism of uremic rats. MAIN METHODS: 45 healthy SD rats were randomly divided into 3 groups: Normal group (n=15), CRF group (n=15), CRF diet supplemented with 2% La (n=15). AMC in great arteries were evaluated by VonKossa. Osteochondrogenic specific genes were analyzed by Immunohistochemistry and qRT-PCR. Serum FGF-23 and klotho levels were detected by ELISA kit. KEY FINDINGS: Serum phosphate was markedly increased in CRF group (6.94 ± 0.97 mmol/L) and 2%La group (5.12 ± 0.84 mmol/L) at week 4, while the latter became hypophosphatemic (2.92 ± 0.73 mmol/L vs CRF group, p<0.01) at week 10. Inhibitory effect of 2%La on development of AMC was reflected by downregulated Runx2, Osterix, BSP, Osteocalcin and collagenII and a reduction of FGF-23 at week 4(vs CRF group, p<0.01) but not week 10. SIGNIFICANCE: Beneficial effects of Lanthanum carbonate on progression of AMC in CRF could be mainly due to the decreased phosphate retention and FGF-23 in early stage and likewise a reduction of bone-associated proteins via osteochondrogenic pathway. Lanthanum carbonate has no effect on soluble klotho and serum FGF-23 in late stage of CRF.

[In vitro effect of the S3Pvac vaccine against cysticercosis in human mononucleate cells]. / Efecto in vitro de la vacuna S3Pvac contra cisticercosis en celulas mononucleares humanas.

INTRODUCTION: Neurocysticercosis (NCC) is a parasitic infection caused by the establishment of Taenia solium cysticerci in the central nervous system. The larval stage of the parasite also affects the pig, which is the essential intermediate host for transmission. For this reason, many researchers have focused on identifying protective antigens to prevent swine cysticercosis and interrupt the transmission. These include S3Pvac vaccine antigens. Vaccine is constituted by three protective synthetic peptides: KETc1, KETc12 and GK1. AIM. To evaluate the effect of the vaccine peptides KETc1, KETc12 and GK1 in mononuclear cells of patients with neuro-cysticercosis and healthy individuals. SUBJECTS AND METHODS: Comparative, prospective, transverse study. We studied the proliferation and cytokine profile induced by the three peptides in mononuclear cells from three patients with active NCC, 16 patients by calcified NCC and 16 healthy subjects. RESULTS: KETc1 induces low levels of proliferation in cells from patients with active and controlled NCC, both in lymphocytes and in monocytes. KETc12 and GK-1 induce positive proliferation levels of monocytes in healthy subjects. CONCLUSIONS: KETc1 peptide could be used as an adjuvant in the treatment of patients with active NCC, as induced a Th2 response also GK1 peptide as stimulator of monocyte/macrophage in immunizations with other proteins.

TITLE: Efecto in vitro de la vacuna S3Pvac contra cisticercosis en celulas mononucleares humanas.Introduccion. La neurocisticercosis (NCC) es una infeccion parasitaria generada por el establecimiento de cisticercos de Taenia solium en el sistema nervioso central. La fase larvaria del parasito tambien afecta al cerdo, que es el huesped intermediario indispensable para la transmision. Por tal motivo, muchos investigadores se han enfocado en identificar antigenos protectores para prevenir la cisticercosis porcina e interrumpir la transmision. Entre ellos figuran los antigenos de la vacuna S3Pvac, constituida por tres peptidos protectores: KETc1, KETc12 y GK1. Objetivo. Evaluar el efecto de los peptidos vacunales KETc1, KETc12 y GK1 en celulas mononucleares de pacientes con NCC e individuos sanos. Sujetos y metodos. Estudio comparativo, prospectivo y transversal. Se analizo la proliferacion y el perfil de citocinas inducidos por los tres peptidos en celulas mononucleares de tres pacientes con NCC activa, 16 pacientes con NCC calcificada y 16 sujetos sanos. Resultados. KETc1 induce bajos niveles de proliferacion en las celulas de los pacientes con NCC activa y controlada, tanto en linfocitos como en monocitos. KETc12 y GK-1 inducen niveles positivos de proliferacion de monocitos en sujetos sanos. Conclusiones. El peptido KETc1 podria usarse como coadyuvante en el tratamiento de los pacientes con NCC activa, ya que indujo una respuesta Th2; y el peptido GK1, como estimulador del monocito/macrofago en inmunizaciones con otras proteinas.