Markers Of Mineral Metabolism Research Articles

Serum Alkaline Phosphatase Level Predicts Cardiac Valve Calcification in Maintenance Hemodialysis Patients

Purpose: Cardiac valve calcification (CVC) is frequently occurred in maintenance hemodialysis (MHD) patients and is associated with cardiovascular and all-cause mortality. This study aimed to evaluate the relationships between risk factors and extent of CVC and further provide the treatment target in MHD patients. Methods: One hundred and forty-five patients who received MHD ≥3 months were enrolled. CVC was assessed by an echocardiographic, semi-quantitative manner called global cardiac calcium scoring system (GCCS), and demographic, clinical, and laboratory parameters including mineral metabolism markers were collected. Results: The average age of the patients was 50 ± 12 years, and 54.5% were men. The mean GCCS was 1.8 ± 2.4; 57.2% of patients had GCCS ≥1. Age, dialysis vintage, serum alkaline phosphatase (ALP), and intact parathyroid hormone levels were positively correlated with CVC, whereas serum albumin levels were negatively related to CVC, based on univariate analysis. With multivariate linear regression analysis, serum ALP was the only bone-derived biomarker that showed significant correlation with CVC. Serum ALP ≥232 U/L was a robust predictor of CVC and was associated with the likelihood of GCCS ≥1 (OR 3.92, 95% CI 1.37–11.2, p = 0.011). The decision tree model was used to identify ALP ≥232 U/L and age ≥60 years as important determinative variables in the prediction of CVC in MHD patients. Conclusion: Serum ALP level is significantly associated with CVC in MHD patients. ALP is suggested to be a promising interventional target for cardiovascular calcification in MHD patients.

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

BackgroundAlthough 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.MethodsThe 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.ResultsBaseline 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).ConclusionsIn 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.

Free 25-hydroxyvitamin-D concentrations are lower in children with renal transplant compared with chronic kidney disease

BackgroundTotal serum 25-hydroxyvitamin D [25(OH)D] is considered the best marker of vitamin D status and used routinely in clinical practice. However, 25(OH)D is predominantly bound to vitamin D-binding protein (VDBP), and it has been reported that the free-25(OH)D and 25(OH)D loosely bound to albumin fraction correlates better with clinical outcomes.MethodsWe assessed total-25(OH)D, measured free-25(OH)D, and calculated free-25(OH)D and their relationship with VDBP and biomarkers of mineral metabolism in 61 children (22 CKD 2–3, 18 dialysis, and 21 post-transplant).ResultsTotal-25(OH)D concentrations were comparable across the three groups (p = 0.09), but free- and bioavailable-25(OH)D (free- and albumin-25(OH)D) were significantly lower in the transplant group (both: p = 0.01). Compared to CKD and dialysis patients, the transplant group had significantly higher VDBP concentrations (p = 0.03). In all three groups, total-25(OH)D concentrations were positively associated with measured free-, calculated free-, and bioavailable-25(OH)D. Multivariable regression analysis showed that total-25(OH)D was the only predictor of measured free-25(OH)D concentrations in the dialysis group (β = 0.9; R2 = 90%). In the transplant group, measured free-25(OH)D concentrations were predicted by both total-25(OH)D and VDBP concentrations (β = 0.6, − 0.6, respectively; R2 = 80%). Correlations between parathyroid hormone with total-25(OH)D and measured and calculated free-25(OH)D were only observed in the transplant group (all: p < 0.001).ConclusionsIn transplanted patients, VDBP concentrations were significantly higher compared to CKD and dialysis patients, and consequently, free-25(OH)D concentrations were lower, despite a comparable total-25(OH)D concentration. We suggest that free-25(OH)D measures may be required in children with CKD, dialysis, and transplant, with further research required to understand its association with markers of mineral metabolism.

A study of vitamin D status in Egyptian pediatric epileptic patients on monotherapy antiepileptic drugs: a hospital-based study

Introduction and aim Epilepsy is a chronic condition with an incidence of 4–10/1000 worldwide. Antiepileptic drugs (AEDs) remain the mainstay of treatment for epilepsy. AEDs in common use are carbamazepine (CBZ), phenytoin, phenobarbitone, and sodium valproate. Long-term therapy by AEDs is associated with bone disorders, affected by both duration and dose of these drugs. The effect of antiepileptic on serum vitamin D levels is controversial and uncertain, so further clinical studies to ascertain the effect of old and newer AEDs on serum levels of vitamin D level in epileptic patients are needed, thus accomplishing a suitable usage of vitamin supplementation. The aim of this study is to assess the longitudinal effect of AEDs on serum 25-hydroxyvitamin D [25(OH) D] levels and bone mineral metabolism markers among Egyptian pediatric epileptic patients on monotherapy AEDs. Participants and methods The study was carried out on 62 epileptic patients attending the Neuropediatric Outpatient Clinic, Children's Hospital Cairo University, with history of seizures (age ranges from 1 year up to 12 years), and 64 children not on AEDs as a control group. Daily dietary intake of calories, calcium, and phosphorus was characterized by dietary recall method. Patients on valproate were 37.1% of patients, whereas 32.3% were on levetiracetam and 30.6% were on CBZ. Valproate dose ranged between 10 and 40 mg/kg/day, with a mean dose of 30.4 ± 8.1 mg/kg/day, whereas levetiracetam dose ranged between 20 and 50 mg/kg/day, with a mean dose of 26 ± 8.8 mg/kg/day, and CBZ dose ranged between 15 and 40 mg/kg/day, with a mean dose of 31.8 ± 8.9 mg/kg/day. All patients on AED and control group were evaluated for vitamin D level. Serum calcium, phosphorus, Mg, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, and urea were measured for both patient and control groups. Results Marked vitamin D deficiency was detected in 31 epileptic patients (50%) (mean ± SD: 13.4 ± 7.6 ng/ml) compared with the control group (6.2%) (mean ± SD: 60.4 ± 17.9 ng/ml) (P = 0.000), whereas mild deficiency was remarkable in 19 patients with epilepsy (30.6%) compared with five (7.8%) controls. Overall, 54.8% of the severely deficient patients in vitamin D were on CBZ, whereas 41.9% were on valproate, and 3.2% were on levetiracetam, with statistical significance on comparing vitamin D level with the type of AEDs (P

Markers of mineral metabolism and vascular access complications: The Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study.

Vascular access dysfunction is a major cause of morbidity in patients with end-stage renal disease (ESRD) on chronic hemodialysis. The effects of abnormalities in mineral metabolism on vascular access are unclear. In this study, we evaluated the association of mineral metabolites, including 25-hydroxy vitamin D (25(OH)D) and fibroblast growth factor-23 (FGF-23), with vascular access complications. We included participants from the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study who were using an arteriovenous fistula (AVF; n = 103) or arteriovenous graft (AVG; n = 116). Serum levels of 25(OH)D, FGF-23, parathyroid hormone (PTH), calcium, phosphorus, C-reactive protein (CRP) and interleukin-6 (IL-6) were assessed from stored samples. Participants were followed for up to 1 year or until a vascular access intervention or replacement. A total of 24 participants using an AVF and 43 participants using an AVG experienced access intervention. Those with 25(OH)D level in the lowest tertile (<11 ng/mL) had an increased risk of AVF intervention compared to those with higher 25(OH)D levels (adjusted relative hazard [aHR] = 3.28; 95% confidence interval [CI]: 1.31, 8.20). The highest tertile of FGF-23 (>3750 RU/mL) was associated with greater risk of AVF intervention (aHR = 2.56; 95% CI: 1.06, 6.18). Higher PTH was associated with higher risk of AVF intervention (aHR = 1.64 per SD of log(PTH); 95% CI: 1.02, 2.62). These associations were not observed in participants using an AVG. None of the other analytes were significantly associated with AVF or AVG intervention. Low levels of 25(OH)D and high levels of FGF-23 and PTH are associated with increased risk of AVF intervention. Abnormalities in mineral metabolism are risk factors for vascular access dysfunction and potential therapeutic targets to improve outcomes.

Effectiveness of Native Vitamin D Therapy in Patients with Chronic Kidney Disease Stage 3 and Hypovitaminosis D in Colombia, South America.

Introduction: In a high percentage of patients with chronic kidney disease (CKD) low levels of vitamin D are detected. The purpose of this study was to evaluate if the native vitamin D therapy (cholecalciferol) in the patients with stage 3 and hypovitaminosis D allows to modify markers of bone and mineral metabolism once normal serum levels have been achieved.Materials and methodsFrom an initial base of 297 patients with CKD and hypovitaminosis D, those with normal or high levels of PTH were chosen for therapy with native vitamin D. The initial administered dose was 1000 IU/day, with adjustments every 4 months of 1000 IU (maximum 4000 IU/day, according to RDA and IOM), until achieving serum levels of 25 hydroxyvitamin D greater than 30 ng/mL and lower than 80 ng/mL. The variables calcium, phosphorus, intact parathormone (iPTH), creatinine and glomerular filtration rate (GFR) were also evaluated every 4 months.ResultsThe total number of patients included in this study was 170. Seventy-three patients were excluded along the follow-up: 17 non-responders (never achieved the projected serum levels of vitamin D), and 56 for not completing one year of follow-up. A total of 97 patients were finally included. In 82 patients, follow-up was achieved for 12 months (G1) and in 38 patients for 24 months (G2). In 15 patients despite achieving satisfactory levels of vitamin D at 12 months, it was not possible to obtain adequate levels of iPTH for their GFR according to K/DOQI 2003 guidelines and they were called refractory to therapy (G3). In both groups 1 and 2, a non-significant tendency to increase calcium and serum phosphorus was observed. iPTH decreased significantly at 12 and 24 months follow-up. In group 3, we opted at 12 months for conversion to calcitriol, with a significant reduction in iPTH values. In this group, the initial value of GFR was close to 30 mL/min, and its fall in time more significant than the other two groups to CKD stage 4.ConclusionCholecalciferol with adjustment in its dose, and obtaining normal serum levels is an excellent therapeutic alternative for the treatment of patients with CKD stage 3, and hypovitaminosis D. In the group of patients with GFR close to 30 mL/min, or lower values (stage 4), and with the presence of secondary hyperparathyroidism, the use of active form of vitamin D (calcitriol, paricalcitol) is recommended as the first therapeutic alternative.

Parathyroid Hormone and Plasma Phosphate Are Predictors of Soluble α-Klotho Levels in Adults of European Descent.

α-klotho is an integral membrane protein that serves as a coreceptor for fibroblast growth factor 23 (FGF23) in conjunction with cognate fibroblast growth factor receptors. Proteolytic cleavage sheds the ectodomain of α-klotho (soluble α-klotho) as an endocrine substance into blood, urine, and cerebrospinal fluid. To study the relationship of soluble α-klotho to mineral metabolism in the general population with mainly preserved kidney function. Cross-sectional analysis of the associations between soluble α-klotho with laboratory markers of markers of mineral metabolism in a population-based cohort. Three centers in Switzerland including 1128 participants. Soluble full-length α-klotho levels by a specific immunoassay and markers of mineral metabolism. The median serum level of soluble α-klotho was 15.0 pmol/L. Multivariable analyses using α-klotho as the outcome variable revealed a sex-by-PTH interaction: In men, PTH was positively associated with α-klotho levels, whereas this association was negative in women. Plasma phosphate associated with soluble α-klotho levels in an age-dependent manner, changing from a positive association in young adults gradually to a negative association in the elderly. The decline of 1,25 (OH)2 vitamin D3 levels in parallel to the gradual impairment of kidney function was greatly attenuated in the setting of high circulating soluble α-klotho levels. Soluble α-klotho level is associated with plasma phosphate in an age-dependent manner and with PTH in a sex-dependent manner. Furthermore, our data reveal soluble α-klotho as a modulator of 1,25 (OH)2 vitamin D3 levels in individuals with preserved renal function.

Impact of Race on the Association of Mineral Metabolism With Heart Failure: the Multi-Ethnic Study of Atherosclerosis.

Alterations in mineral metabolism, such as high phosphorus, high parathyroid hormone (PTH), and high fibroblast growth factor-23 (FGF-23) have been identified as potential risk factors for heart failure (HF). Important differences in the prevalence of mineral metabolism abnormalities and in the risk of HF have been reported across race and/or ethnic groups. In this study, we evaluated whether the associations of mineral metabolism markers with HF differed by race and/or ethnicity. We included participants free of cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis to quantify rates of HF overall and across race and/or ethnic groups. Using Cox models, we tested associations of baseline higher phosphorus (>4 mg/dL), PTH greater than 65 pg/mL, and FGF-23 greater than 46.5 pg/mL with incident HF, and for interactions by race and/or ethnicity, adjusting for sociodemographic and cardiovascular risk factors. Among the 6413 participants, median follow-up time was 14.9 years. The incidence rate for HF was highest for African Americans and lowest for Chinese (4.71 and 2.42 per 1000 person-years, respectively). The prevalence of elevated PTH (18.8% vs 7.4%) but not FGF-23 (23.1% vs 28.8%) was higher in African Americans vs Whites. In multivariable models, the associations of elevated PTH (hazard ratio [HR] 1.50, 95% CI: 1.13-1.99) and FGF-23 (HR 1.37, 95% CI: 1.07-1.75) with incident HF were statistically significant. However, the interactions by race and/or ethnicity were not statistically significant. In a multiethnic population, higher PTH and FGF-23 were associated with risk of HF in African American and Hispanic individuals. There is no evidence that race and/or ethnicity modifies the association of altered mineral metabolism with risk of HF.

Interplay of nitric oxide metabolites and markers of endothelial injury, inflammation, and vascular disease in the spectrum of advanced chronic kidney disease.

Chronic kidney disease is linked to cardiovascular morbidity; therefore, relevant biomarkers are widely investigated. We aimed to assess the relationship between nitric oxide (as measured by its metabolites, NOx), a key endothelial molecule, with markers of endothelial dysfunction, inflammation, antioxidant status, and mineral disorders as well as histologically assessed vascular calcification in uremic and hemodialysis patients with chronic kidney disease. Plasma and serum samples were obtained from 62 patients with renal failure. NOx was assessed by the Griess method, while the other biomarkers were measured by the immunoenzymatic assay. Morphological analysis of arterial calcification was performed in a blinded, semiquantitative manner. Common carotid intima‑media thickness and atherosclerotic plaques were assessed by ultrasonography. In the simple analysis, NOx levels correlated positively with the parameters of renal function, mineral metabolism, endothelial injury, and inflammation. NOx predicted carotid intima‑media thickness in simple (P = 0.014) and multiple analysis (P = 0.036) adjusted for the Framingham risk score, C‑reactive protein, serum creatinine, and parathormone. The occurrence of atherosclerotic plaques in the common carotid artery was correlated with higher NOx concentrations (P = 0.021). In chronic renal failure, NOx is associated with surrogate markers of atherosclerosis, even after adjustment for traditional cardiovascular risk factors, inflammation, and renal function, but not with the presence or grade of medial arterial calcification. Endothelial injury, inflammation, and mineral metabolism markers are associated with NOx levels, though a causal link requires further study.

Effect of Oat β-Glucan Supplementation on Chronic Kidney Disease: A Feasibility Study

Dietary supplementation with grains containing high β-glucan fiber has been shown to attenuate the progression of chronic kidney disease (CKD) and vascular calcification in animal models. The aim of this study was to investigate the feasibility of consuming an oat β-glucan supplement and to assess its effects on certain uremic toxins and markers of mineral metabolism in patients with CKD. This is a 20-week, nonrandomized, single-center, pretest-posttest study. Twenty-eight subjects with CKD stages 3-4 were enrolled. The mean age was 67.6±8.9years, and the mean estimated glomerular filtration rate was 35±14mL/min/1.73m2. Subjects received a dietary supplement containing 3g of oat β-glucan per day for 12weeks. The 4-week period before the start of the intervention was used as a baseline comparison for each subject. The primary outcome was pre-post supplement changes in plasma levels of two uremic toxins: trimethylamine N-oxide (TMAO) and asymmetric dimethylarginine. Secondary outcomes were pre-post supplement changes in serum calcium, phosphorus, and Klotho levels. Repeated-measures analysis of variance was used to test the differences in outcomes over the three-month-long intervention. Serum levels of TMAO decreased by a median of -17% (interquartile range: -46%, 7%) at the end of the intervention. A nonstatistically significant change was observed for asymmetric dimethylarginine (median -0.6% [-12%, 20%]) and serum Klotho (median -3% [-8%, 7%]). There were no changes in serum levels of calcium and phosphorus. One month after discontinuation of β-glucan therapy, TMAO levels increased by a median of 16% (-12%, 36%) but remained slightly below the pretreatment levels. Eight subjects experienced side effects and discontinued the treatment. A diet supplemented with β-glucan is safe and potentially efficacious in lowering serum concentrations of TMAO in patients with CKD. Larger trials with longer follow-up times are needed to determine whether such reductions translate into clinical benefits.

Longitudinal Evolution of Markers of Mineral Metabolism in Patients With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study

The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD. Retrospective analysis nested in a cohort study. Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had up to 5 serial annual measurements of estimated glomerular filtration rate, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), serum phosphate, and serum calcium and who subsequently reached end-stage kidney disease (ESKD) during follow-up (n= 847). Years before ESKD. Serial FGF-23, PTH, serum phosphate, and serum calcium levels. To assess longitudinal dynamics of disordered mineral metabolism in human CKD, we used "ESKD-anchored longitudinal analyses" to express time as years before ESKD, enabling assessments of mineral metabolites spanning 8 years of CKD progression before ESKD. Mean FGF-23 levels increased markedly as time before ESKD decreased, while PTH and phosphate levels increased modestly and calcium levels declined minimally. Compared with other mineral metabolites, FGF-23 levels demonstrated the highest rate of change (velocity: first derivative of the function of concentration over time) and magnitude of acceleration (second derivative). These changes became evident approximately 5 years before ESKD and persisted without deceleration through ESKD onset. Rates of changes in PTH and phosphate levels increased modestly and without marked acceleration around the same time, with modest deceleration immediately before ESKD, when use of active vitamin D and phosphate binders increased. Individuals who entered the CRIC Study at early stages of CKD and who did not progress to ESKD were not studied. Among patients with progressive CKD, FGF-23 levels begin to increase 5 years before ESKD and continue to rapidly accelerate until transition to ESKD.

Markers of Bone Mineral Metabolism and Cardiac Structure and Function in Perinatally HIV-Infected and HIV-Exposed but Uninfected Children and Adolescents.

Disordered bone mineral metabolism and low vitamin D concentrations are associated with cardiovascular abnormalities; few studies have evaluated this relationship in HIV-infected youth. The Adolescent Master Protocol is a Pediatric HIV/AIDS Cohort Study network study conducted across 14 US sites. Among perinatally HIV-infected (PHIV) and perinatally HIV-exposed but uninfected (PHEU) youth enrolled in the Adolescent Master Protocol, we evaluated associations of vitamin D [measured as 25-hydroxy-vitamin D (25-OHD)], parathyroid hormone (PTH), calcium, phosphate, and fibroblast growth factor-23 (FGF-23) concentrations with echocardiographic measures of left ventricular (LV) structure, function, and concentrations of NT-proBNP, a biomarker of cardiac damage. Among 485 participants (305 PHIV and 180 PHEU) with echocardiograms and bone mineralization measures, low 25-OHD (<20 ng/mL) was common among all participants (48% PHIV and 44% PHEU), but elevated PTH (>65 pg/mL) was identified more often among PHIV participants than PHEU participants (9% vs 3%, P = 0.02). After adjusting for HIV status and demographic covariates, both low 25-OHD and elevated PTH were associated with lower mean LV mass z-scores, whereas elevated PTH was associated with higher mean fractional shortening z-scores. Participants with low 25-OHD also had slightly higher mean LV end-systolic wall stress z-scores, but differences were more pronounced in PHEU participants than in PHIV participants. FGF-23 was inversely related to end-diastolic septal thickness, both overall and among PHIV participants. In this cohort of PHIV and PHEU youth, we observed associations of 25-OHD, PTH, and FGF-23 with both structural and functional cardiac parameters, supporting links between bone mineral metabolism and cardiac status.

Associations between serum mineral metabolism parameters and mortality in patients on peritoneal dialysis.

Disturbances in mineral metabolism markers are common in patients with chronic kidney disease but there is no consensus on the association between these markers and clinical outcomes. This study investigated associations between mineral metabolism parameters and mortality in Chinese peritoneal dialysis (PD) patients. This was a single-centre retrospective cohort study. Incident PD patients between 1 January 2006 and 31 December 2013 with baseline phosphate, albumin-corrected calcium, and calcium-phosphate product data were enrolled. Associations between these parameters and all-cause and cardiovascular mortality were assessed using multivariable-adjusted Cox models. Of 1662 patients (mean age: 47.4 ± 15.3 years), 59.3% were male and 23.8% had diabetes. Over a median 38.1 month (interquartile range: 21.3-59.7 months) follow-up period, 382 (23.0%) patients died. After adjusting for confounders, the higher serum phosphate level (>1.78 mmol/L) and calcium-phosphate product level (≥4.4 mmol2 /L2 ) were significantly associated with an increased risk for all-cause mortality (hazards ratio (HR) = 1.818, 95% CI = 1.379-2.396 and HR = 1.735, 95% CI = 1.261-2.386) and cardiovascular mortality (HR = 2.069, 95% CI = 1.428-2.998 and HR = 2.175, 95% CI = 1.450-3.262), respectively. While each 1 mmol/L higher baseline albumin-corrected calcium level was associated with an 14.3% (95% CI = 0.749-0.981) lower risk for all-cause mortality after adjusting for potential confounders. Abnormalities in mineral metabolism markers, particularly higher serum phosphate and calcium-phosphate product levels, at the commencement of PD were independently associated with increased all-cause and cardiovascular mortality in this cohort of PD patients.

Mineral Metabolism Disturbances and Arteriovenous Fistula Maturation

The arteriovenous fistula (AVF) is central to haemodialysis treatment, but up to half of surgically created AVF fail to mature. Chronic kidney disease often leads to mineral metabolism disturbances that may interfere with AVF maturation through adverse vascular effects. This study tested associations between mineral metabolism markers and vein histology at AVF creation and unassisted and overall clinical AVF maturation. Concentrations of fibroblast growth factor 23, parathyroid hormone, calcium, phosphate, and vitamin D metabolites: 1,25(OH)2D, 24,25(OH)2D, 25(OH)D, and bioavailable 25(OH)D were measured in pre-operative serum samples from 562 of 602 participants in the Haemodialysis Fistula Maturation Study, a multicentre, prospective cohort study of patients undergoing surgical creation of an autologous upper extremity AVF. Unassisted and overall AVF maturation were ascertained for 540 and 527 participants, respectively, within nine months of surgery or four weeks of dialysis initiation. Study personnel obtained vein segments adjacent to the portion of the vein used for anastomosis, which were processed, embedded, and stained for measurement of neointimal hyperplasia, calcification, and collagen deposition in the medial wall. Participants in this substudy were 71% male, 43% black, and had a mean age of 55 years. Failure to achieve AVF maturation without assistance occurred in 288 (53%) participants for whom this outcome was determined. In demographic and further adjusted models, mineral metabolism markers were not significantly associated with vein histology characteristics, unassisted AVF maturation failure, or overall maturation failure, other than a biologically unexplained association of higher 24,25(OH)2D with overall failure. This exception aside, associations were non-significant for continuous and categorical analyses and relevant subgroups. Serum concentrations of measured mineral metabolites were not substantially associated with major histological characteristics of veins in patients undergoing AVF creation surgery, or with AVF maturation failure, suggesting that efforts to improve AVF maturation rates should increase attention to other processes such as vein mechanics, anatomy, and cellular metabolism among end stage renal disease patients.

Increased acute vascular deposition of radioactive phosphate is an index of calcification

Mineral bone disorder and vascular calcification (VC) are substantial contributors to the elevated cardiovascular disease (CVD) burden in chronic kidney disease patients. The degree to which the uremic milieu and mineral dysregulation individually contribute to this CVD is poorly understood. Calcitriol, the active form of vitamin D, is a key regulator of mineral metabolism. In this study, we present a model of rapid calcitriol‐induced VC in rats with normal kidney function, with findings that point to active and non‐active processes of calcification being fundamentally different phenotypes.Male Sprague Dawley rats (n=17, 15 weeks) were injected with 0.5 μg/kg/day calcitriol SQ for 8 days. On the 9th day, half of the animals were sacrificed (n=8, CxE), and the remainder were sacrificed 14 days after the cessation of calcitriol (n=9, CxL). Control animals (n=6) followed the same protocol. Circulating calcium, phosphate, and hormones regulating mineral metabolism (parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF‐23)) were measured every two days. At sacrifice, animals underwent an IV infusion of 300μmol PO4 spiked with radioactive 33PO4. Forty body tissues, including 14 across the vascular tree, were harvested and analyzed for mineral content/VC (calcium and phosphate) as well as acute phosphate deposition (33PO4 accrual).Daily administration of high‐dose calcitriol significantly elevated FGF‐23 and calcium, and suppressed PTH after only 2 doses, however, 14 days after calcitriol withdrawal, the analytes had fully normalized (Figure 1). Substantial VC was generated over the 8 days of treatment (7.8±4.2 v. 166±142 nmol Ca/mg tissue, p&lt;0.001) and persisted 14 days after stopping treatment (540±492 nmol Ca/mg tissue). Following IV infusion of phosphate labelled with 33PO4, animals sacrificed directly following calcitriol treatment (CxE) had greater accrual of phosphate acutely in the vascular bed compared to those sacrificed 14 days after the cessation of treatment (CxL; −50.4%, p&lt;0.001), despite having sustained levels of resident VC (Figure 2).Despite the similar magnitude of VC, acute deposition of phosphate following the IV load, a potential measure of calcification activity, was significantly greater during calcitriol treatment (CxE) than after stopping it (CxL). This suggests that the VC itself does not mediate the increased accrual of phosphate, but rather the cellular phenotype of the tissue. Also, it was this acute activity, not the resident VC, that aligned with dysregulated mineral metabolism markers. The transcriptional, cellular, and physiological differences of these two states, as well as their differential associations with circulating analytes are not currently differentiated in VC research. These differences likely have an important role in VC present in humans.Support or Funding InformationThis research was funded by Canadian Institutes of Health Research and Vanier Canada Graduate Scholarships.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Diabetes Mellitus Modifies the Associations of Serum Magnesium Concentration With Arterial Calcification and Stiffness in Incident Hemodialysis Patients

IntroductionMagnesium (Mg) may protect against arterial calcification. We tested the hypotheses that a higher serum Mg concentration is associated with less arterial calcification and stiffness in patients on hemodialysis (HD) and that these associations are modified by diabetes mellitus.MethodsWe performed cross-sectional analyses of 367 incident HD patients from the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) cohort. Measures of arterial calcification and stiffness included coronary arterial calcification (CAC) and thoracic aortic calcification (TAC) scores, ankle brachial index (ABI; high ABI: >1.4 or incompressible vessels), pulse wave velocity (PWV), and pulse pressure.ResultsMean Mg was 1.8 ± 0.2 mEq/l and 58% had diabetes. Among nondiabetic individuals, per 0.1 mEq/l higher Mg, non-zero CAC score was lower (% difference: −15.4%; 95% confidence interval [CI]: −28% to −0.55%; P = 0.03), the odds of having TAC score >0 and the odds of having high ABI were lower (odds ratio [OR]: 0.66; 95% CI 0.47–0.93; P = 0.02, and 0.23; 95% CI: 0.06–0.83, P = 0.03, respectively) while adjusting for demographics, comorbidities, markers of mineral metabolism, and dialysis clearance. Among diabetic individuals, per 0.1 mEq/l higher Mg, the odds of having TAC score >0 was higher (OR: 1.57; 95% CI: 1.09–2.26; P = 0.02). Mg was not associated with CAC or high ABI among diabetic individuals. Mg was not associated with PWV or pulse pressure regardless of diabetes status.ConclusionDiabetes modified the associations of serum Mg with arterial calcification and stiffness in incident HD patients. Higher Mg was associated with less arterial calcification and less peripheral arterial stiffness among nondiabetic individuals, but Mg was only associated with TAC among diabetic individuals with higher Mg being associated with higher likelihood of having TAC score >0.

Correlation between Aortic Calcification Score and Biochemical Parameters in Hemodialysis Patients.

The purpose of this study was to determine the correlation between aortic calcification and demographic and biochemical parameters in hemodialysis patients. Calcification scores of the aortic arch and abdominal aorta were determined from multi-slice computed tomography scans and evaluated according to the Agatston score. The associations between demographic and biochemical parameters and aortic calcification score were determined. In total, 190 patients were included in the study. There was a significant positive correlation between aortic calcification scores and age, duration of hemodialysis, cardiothoracic ratio, normalized protein catabolic rate, brachial-ankle pulse wave velocity (baPWV), serum markers of mineral metabolism, and inflammation. A significant negative correlation was found between aortic calcification scores and platelet count. Multivariate analysis showed that age, duration of hemodialysis, baPWV, phosphate, calcium and phosphate (Ca×P) product, parathyroid hormone, and C-reactive protein levels were independent risk factors for calcification of the aortic arch, while baPWV and Ca×P product were independent risk factors for calcification of the abdominal aorta. Key Messages: Aortic calcification scores correlate with age, duration of hemodialysis, and several biochemical parameters of inflammation and mineral metabolism.

Association of Bone Mineral Density With Fractures Across the Spectrum of Chronic Kidney Disease: The Regina CKD-MBD Study.

Background:Recent studies have demonstrated that measurement of areal bone mineral density by dual-energy x-ray absorptiometry (DXA) predicts fractures in patients with chronic kidney disease (CKD). However, whether fracture risk prediction through bone mineral density (BMD) is enhanced due to the assessment of biochemical markers of chronic kidney disease and mineral and bone disease (CKD-MBD) or clinical risk factors is not clear. We hypothesized that in a select cohort of patients managed in a CKD clinic, that combining T-Scores with biochemical markers would optimize fracture discrimination than using DXA alone.Objective:To examine the relationships among BMD, biochemical markers of CKD-MBD, and fracture risk across Kidney Disease Improving Global Outcomes (KDIGO) glomerular filtration rate (GFR) categories G3a to G5.Design:Retrospective study.Setting:Patients were recruited from the multidisciplinary CKD clinic, Regina General Hospital, Canada.Patients:A total of 374 patients who received a DXA scan upon initial referral to Regina Multidisciplinary CKD Program from January 31, 2001 to January 31, 2010, were included in this study. The patients were followed for a total of 5 years.Methods:We conducted a retrospective review of 374 consecutive patients who underwent DXA imaging at the point of entry into our multidisciplinary CKD program. Areal BMD, T- and Z-Scores were obtained at the lumbar spine, total hip, mean of left and right femoral neck, and the one-third radius. We collected data on demographic, cross-sectional biochemical markers of mineral metabolism and fractures (identified through self-reported questionnaires, hospital electronic medical records, and physician billing records). We were able to gather data on 8/11 variables of Fracture Risk Assessment (FRAX) tool.Results:In our cohort, 14.3% of GFR categories G3a and G3b, 15.7% of GFR category G4, and 19.7% of GFR category G5 experienced a clinical fracture during the study period. On multivariate analysis, each decline of 1.0 SD in total hip BMD T-Score was associated with a significant increase in the risk of fracture (OR = 1.46, 95% confidence interval [CI], 1.12-1.89). Adding CKD-MBD markers and clinical risk factors did not further contribute to the model. Low BMD was the only independent risk factor for fracture in patients with CKD.Limitations:Self-reporting by patients and administrative records were used to identify fractures. We did not perform spine imaging to ascertain morphometric vertebral fractures. We were unable to gather all 11 variables of FRAX score and information on ethnicity. We were unable to capture site of fracture (hips, spine, etc) from billing records. Albumin excretion rates were not collected at baseline. Treatment of the underlying bone disease with pharmacotherapeutic agents may have attenuated patients’ fracture risk and thus underestimated the association between BMD and future fracture.Conclusions:Our findings confirm that BMD predicts fracture. The addition of cross-sectional CKD-MBD parameters and clinical risk factors to BMD did not add to fracture prediction. Prospective studies should investigate the utility of longitudinal biochemical markers on improving fracture risk assessment.

The impact of cinacalcet in the mineral metabolism markers of patients on dialysis with severe secondary hyperparathyroidism.

Introduction:Treating secondary hyperparathyroidism (SHPT), a common condition associated with death in patients with chronic kidney disease, is a challenge for nephrologists. Calcimimetics have allowed the introduction of drug therapies no longer based on phosphate binders and active vitamin D. This study aimed to assess the safety and effectiveness of cinacalcet in managing chronic dialysis patients with severe SHPT. Methods: This retrospective study included 26 patients [age: 52 ± 12 years; 55% females; time on dialysis: 54 (4-236) months] on hemodialysis (N = 18) or peritoneal dialysis (N = 8) with severe SHPT (intact parathyroid hormone (iPTH) level > 600 pg/mL) and hyperphosphatemia and/or persistent hypercalcemia treated with cinacalcet. The patients were followed for 12 months. Their serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and iPTH levels were measured at baseline and on days 30, 60, 90, 180, and 365. Results: Patients with hyperphosphatemia (57.7%), hypercalcemia (23%), or both (19.3%) with iPTH > 600 pg/mL were prescribed cinacalcet. At the end of the study, decreases were observed in iPTH (1348 ± 422 vs. 440 ± 210 pg/mL; p < 0.001), Ca (9.5 ± 1.0 vs. 9.1 ± 0.6 mg/dl; p = 0.004), P (6.0 ± 1.3 vs. 4.9 ± 1.1 mg/dl; p < 0.001), and ALP (202 ± 135 vs. 155 ± 109 IU/L; p = 0.006) levels. Adverse events included hypocalcemia (26%) and digestive problems (23%). At the end of the study, 73% of the patients were on active vitamin D and cinacalcet. Three (11.5%) patients on peritoneal dialysis did not respond to therapy with cinacalcet, and their iPTH levels were never below 800 pg/mL. Conclusion: Cinacalcet combined with traditional therapy proved safe and effective and helped manage the mineral metabolism of patients with severe SHPT.

Natural history of mineral metabolism, bone turnover and bone mineral density in de novo renal transplant recipients treated with a steroid minimization immunosuppressive protocol.

The skeletal effects of renal transplantation are not completely understood, especially in patients managed with a steroid minimization immunosuppressive protocol and long term. We enrolled 69 adult transplant recipients (39 males; ages 51.1 ± 12.2 years), free of antiresorptive therapy and managed with a steroid minimization immunosuppressive protocol, into a 5-year prospective observational study to evaluate changes in areal bone mineral density (aBMD), mineral metabolism and bone remodelling. Dual energy X-ray absorptiometry, laboratory parameters of mineral metabolism (including parathyroid hormone, sclerostin and fibroblast growth factor 23) and non-renal cleared bone turnover markers (BTMs) (bone-specific alkaline phosphatase, trimeric N-terminal propeptide and tartrate-resistant acid phosphatase 5b) were assessed at baseline and 1 and 5 years post-transplantation. The mean cumulative methylprednisolone exposure at 1 and 5 years amounted to 2.5 ± 0.8 and 5.8 ± 3.3 g, respectively. Overall, bone remodelling activity decreased after transplantation. Post-transplant aBMD changes were minimal and were significant only in the ultradistal radius during the first post-operative year {median -2.2% [interquartile range (IQR) -5.9-1.2] decline, P = 0.01} and in the lumbar spine between Years 1 and 5 [median 1.6% (IQR -3.2-7.0) increase, P = 0.009]. BTMs, as opposed to mineral metabolism parameters and cumulative corticosteroid exposure, associated with aBMD changes, both in the early and late post-transplant period. Most notably, aBMD changes inversely associated with bone remodelling changes. In summary, in de novo renal transplant recipients treated with a steroid minimization immunosuppressive protocol, BMD changes are limited, highly variable and related to remodelling activity rather than corticosteroid exposure.