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PubMedDate not supplied

Computed tomography of cerebrovascular calcifications in postsurgical hypoparathyroidism.

Despite the extensive literature on the radiographic appearance of basal ganglia calcification in hypoparathyroidism, the vascular and perivascular deposits that are the hallmark of this disease have not been described radiographically. We report two patients with postsurgical hypoparathyroidism in whom such vascular calcification was observed on CT and was confirmed pathologically in one. The metabolic disturbance leading to the vascular deposits is discussed.

Aged↗
PubMed2005

Sevelamer prevents uremia-enhanced atherosclerosis progression in apolipoprotein E-deficient mice.

BACKGROUND: The novel phosphate binder sevelamer has been shown to prevent the progression of aortic and coronary calcification in uremic patients. Whether it also decreases the progression of atheromatous plaques is unknown. The aim of our study was to examine the effect of sevelamer administration on the development of atherosclerosis and aortic calcification in the uremic apolipoprotein E-deficient mouse as an established model of accelerated atherosclerosis. METHODS AND RESULTS: Female mice were randomly assigned to 4 groups: 2 groups of nonuremic mice (sevelamer versus control) and 2 groups of uremic mice (sevelamer versus control). Sevelamer was given at 3% with chow. The increases in serum phosphorus concentration and calcium-phosphorus product observed in uremic control mice were prevented by sevelamer. Serum total cholesterol was increased in the 2 uremic mouse groups and remained unchanged in response to sevelamer. After 8 weeks of sevelamer treatment, uremic mice exhibited a significantly lower degree of atherosclerosis (P<0.001) and vascular calcification than uremic control mice. Of interest, sevelamer exerted an effect on both intima and media calcification (P=0.005) in uremic mice. Among possible mechanisms involved, we found no evidence for the modulation by sevelamer of inflammation or selected uremic toxins. In contrast, nitrotyrosine staining as a measure of oxidative damage was significantly decreased in response to sevelamer treatment in control and uremic mice (P<0.005). CONCLUSIONS: Sevelamer delays not only vascular calcification but also atherosclerotic lesion progression in uremic apolipoprotein E-deficient mice. It opens the possibility of a cholesterol-independent action of sevelamer on atheroma formation via effects on mineral metabolism, oxidative stress, or both.

Animals↗
PubMed2006

Calcium phosphate metabolism and bone mineral density with nocturnal hemodialysis.

An elevated calcium x phosphate product (Ca x P) is an independent risk factor for vascular calcification and cardiovascular death in dialysis patients. More physiological dialysis in patients undergoing nocturnal hemodialysis (NHD) has been shown to produce biochemical advantages compared with conventional hemodialysis (CHD) including superior phosphate (P) control. Benefits of dialysate with greater calcium (Ca) concentration are also reported in NHD to prevent Ca depletion and subsequent hyperparathyroidism, but there are concerns that a higher dialysate Ca concentration may contribute to raised serum Ca levels and greater Ca x P and vascular disease. The NHD program at our unit has been established for 4 years, and we retrospectively analyzed Ca and P metabolism in patients undergoing NHD (8-9 h/night, 6 nights/week). Our cohort consists of 11 patients, mean age 49.3 years, who had been on NHD for a minimum of 12 months, mean 34.3 months. Commencement was with low-flux (LF) NHD and 1.5 mmol/L Ca dialysate concentration, with conversion to high-flux (HF) dialyzers after a period (mean duration 18.7 months). We compared predialysis serum albumin, intact parathyroid hormone, P, total corrected Ca, and Ca x P at baseline on CHD, after conversion to LF NHD and during HF NHD. We also prospectively measured bone mineral density (BMD) on all patients entering the NHD program. Bone densitometry (DEXA) scans were performed at baseline (on CHD) and yearly after commencement of NHD. With the introduction of HF dialyzers, the Ca dialysate concentration was concurrently raised to 1.75 mmol/L after demonstration on DEXA scans of worsening osteopenia. Analysis of BMD, for all parameters, revealed a decrease over the first 12 to 24 months (N = 11). When the dialysate Ca bath was increased, the median T and Z scores subsequently increased (data at 3 years, N = 6). The mean predialysis P levels were significantly lower on LF NHD vs. CHD (1.51 vs. 1.77 mmol/L, p = 0.014), while on HF NHD P was lower again (1.33 mmol/L, p = 0.001 vs. CHD). Predialysis Ca levels decreased with conversion from CHD to LF NHD (2.58 vs. 2.47 mmol/L, p = 0.018) using a 1.5 mmol/L dialysate Ca concentration. The mean Ca x P on CHD was 4.56 compared with a significant reduction of 3.74 on LF NHD (p = 0.006) and 3.28 on HF NHD (p = 0.001 vs. CHD), despite the higher dialysate Ca in the latter. We conclude that an elevated dialysate Ca concentration is required to prevent osteopenia. With concerns that prolonged higher Ca levels contribute to increased cardiovascular mortality, the optimal Ca dialysate bath is still unknown. Better P control on NHD, however, reduces the overall Ca x P, despite the increased Ca concentration, therefore reducing the risk of vascular calcification.

Adult↗
PubMed2005

[Cardiac failure and diastolic disfunction in hemodialysis patients: associated factors].

UNLABELLED: Heart failure (CHF) and diastolic dysfuction (DD) relationship has received poor attention in hemodialysis patients (HD). OBJECTIVE: To analyse the incidence of CHF in our HD patients, the relationship with DD and impact on mortality. METHODS: We studied 79 patients: 48 +/- 15 years old, mean time on HD 83 +/- 63 months. Vascular calcification (PVC) was evaluated by radiologic series (55.7%). We analyzed the presence of clinical and analytical cardiovascular factors. All patients underwent M-mode, two-dimensional, Doppler echocardiography. Patients were followed for two years. Clinical information collected: incidence of ischemic heart disease (IHD), CHF, and mortality due to cardiovascular events. RESULTS: Most frequent finding was Left Ventricular Hypertrophy (LVH) (93%), followed by DD (63.5% had anormal LV relaxation) (ALVR). Incidence of CHF was 38.3%; and was significantly associated with higher: time on HD (130/72 months), Ca x P (74/65), PTH (677/376), bone alkaline phosphatase (27/16), and systolic BP (145 vs 130 mmHg); IHD, PVC, valvular calcification (VC), LVH and ALVR (p < 0.01). Systolic function was normal in both groups (with/without CHF). Logistic regression identified as risk factors for CHF: ALVR (OR: 9.5), IHD (OR: 15) and systolic BP (OR: 2.2). ALVR was associated with greater age (55/37), longer time on HD (76/60), PVC and VC (p < 0.001). Predictor factors identified were age (OR: 2.13) and PVC (OR: 3.9). CONCLUSIONS: HD patients showed a high incidence of CHF. IHD, systolic BP and DD (ALVR) have behave as risk factors for CHF. Vascular calcifications were intimately related to these findings and, therefore, they contribute to the greater mortality of these patients.

Cross-Sectional Studies↗
PubMedDate not supplied

Role of parathyroid hormone and therapy with active vitamin D sterols in renal osteodystrophy.

Renal osteodystrophy (ROD) represents a spectrum of bone lesions ranging from a high-turnover to a low-turnover state. The expression of the histologic bone lesions is modulated by parathyroid hormone (PTH), vitamin D, calcium, phosphorus, and aluminum that act as major regulators of osteoblastic activity and bone formation rate. The availability of immunometric PTH assays has allowed reasonable prediction of the subtypes of bone lesions in patients with chronic kidney disease (CKD). PTH levels as measured by these assays, however, may not reflect the true bone turnover state during treatment with intermittent active vitamin D. Early diagnosis and appropriate treatment of renal bone disease are essential in preventing the debilitating consequences of ROD on the growing skeleton. Calcitriol and calcium-containing phosphate binders have been the mainstay of treatment for secondary hyperparathyroidism. Complications such as hypercalcemia, vascular calcifications, and the development of adynamic bone may arise from aggressive treatment. New vitamin D analogs and calcium-free phosphate binders are promising in terms of limiting these complications. The management of ROD should be tailored to maintain normal rates of bone formation and turnover with age-appropriate serum calcium and phosphorus levels and with serum PTH levels that correspond to normal rates of skeletal remodeling. These treatment goals would maintain bone health, maximize growth potential, and prevent the development of soft tissue and vascular calcifications.

Chronic Kidney Disease-Mineral and Bone Disorder↗
PubMed2005

IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia--the good, the bad, and the ugly.

It has been increasingly apparent that wasting and cardiovascular disease (CVD) is associated with a persistent systemic inflammatory response in end-stage renal disease (ESRD) patients. The reasons for the increased risk of inflammation in ESRD patients appear to be complex, including non-dialysis as well as dialysis-related factors. The combination of an impaired immune response coupled with persistent immune stimulation may have a role in the low-grade systemic inflammation and altered cytokine balance that characterizes the uremic state and which may translate into increased risk for vascular disease. The accelerated atherosclerotic process of ESRD may involve several interrelated processes, such as oxidative stress, endothelial dysfunction, and vascular calcification, in a milieu of constant low-grade inflammation with impaired function of neutrophils and T cells, as well as a dysregulated cytokine network. Although a large number of pro- and anti-inflammatory cytokines are of importance, available data suggest that the anti-inflammatory cytokine interleukin (IL)-10 and the mainly proinflammatory cytokines IL-6 and tumor necrosis factor-alpha (TNF-alpha) may play important roles in the development of Th imbalance, CVD and wasting in the uremic milieu. Given the strong association between proinflammatory cytokines and complications common in ESRD, such as vascular calcification and wasting, the potential role of both general and targeted anticytokine treatment strategies in ESRD patients needs further evaluation.

Cytokines↗
PubMed2003

Head computed tomography findings predict short-term stroke risk after transient ischemic attack.

BACKGROUND AND PURPOSE: Current guidelines recommend the use of head CT in the evaluation of patients with transient ischemic attack (TIA), but data supporting its value are sparse. METHODS: Patients who presented to 1 of 16 emergency departments of a large Northern California health maintenance organization and received a diagnosis of TIA from November 1997 through February 1998 were enrolled and followed up for 90 days. Clinical, demographic, and outcome data were obtained from computerized databases and medical records. Physicians blinded to patient characteristics and outcomes abstracted head CT findings from radiology reports. Abstracted findings included evidence of old or new infarct, periventricular white-matter disease, cerebral atrophy, cerebral vascular calcification, and nonischemic lesions. RESULTS: Head CT was performed in 67% of eligible patients (n=322) diagnosed with TIA. Evidence of a new infarct was seen on head CT in 13 patients (4%). A nonischemic cause of TIA symptoms was found in 4 patients (1.2%). During follow-up, 10.9% of TIA patients experienced subsequent stroke. After adjustment for confounders, risk for stroke during follow-up was significantly higher in those with a new infarct on head CT compared with others with TIA (odds ratio, 4.06; 95% confidence interval, 1.16 to 14.14; P=0.028). Old infarction, periventricular white-matter disease, cerebral atrophy, and cerebral vascular calcification were not predictors of subsequent risk of stroke. CONCLUSIONS: Evidence of a new infarct on head CT in patients presenting with TIA is associated with increased short-term risk for stroke. Head CT appears to have prognostic value in patients with TIA and, for this reason alone, may be justified in their evaluation.

Adult↗
PubMed2004

[Hyperphosphatemia and cardiovascular risk in patients on dialysis].

Cardiovascular diseases are the leading causes of mortality among patients with end-stage renal disease (ESRD), with arterial disease and left ventricular hypertrophy being the two principal factors of the high mortality rate in this population. In addition to traditional risk factors (age, gender, diabetes, hypertension, lifestyle, hyperlipidemia, smoking, hyperhomocystinemia), inflammation, oxidative stress and disorders of mineral metabolism may contribute to cardiovascular risk in patients with uremic syndrome. High serum phosphate may influence vascular calcifications directly and indirectly, by worsening secondary hyperparathyroidism. Several treatment options are available for the treatment of hyperphosphatemia and secondary hyperparathyroidism in patients with ESRD. The treatment approach includes a diet low in phosphorus, with less than 1 g/kg/day of protein. Vitamin D supplementation is an important part of treatment. Phosphate binding agents are in most of the patients necessary in addition to diet. Aluminum hydroxide has been widely used for many years. It is very potent, but also very toxic, with severe encephalopathy as the most dangerous side effect. Calcium salts are less potent, and were considered safe for use in patients on dialysis. However, improvement in the understanding of vascular calcifications has demonstrated that calcium overload significantly contributes to widespread atherosclerosis in patients with ESRD. Sevelamer-hydrochloride is a novel non-aluminum, non-calcium containing phosphate binder, which is capable of reducing the levels of phosphorus as well as of low-density lipoprotein cholesterol, and increasing high-density lipoprotein cholesterol.

Blood Vessels↗
PubMed2003

[Atherosclerosis and uremia: signifance of non-traditional risk factors].

Arteriosclerosis, atherosclerosis and vascular calcification are causally related to the high morbidity and mortality of patients with chronic renal failure. Oxidative stress and carbonyl stress of uremia, dialysis procedure and/or intravenous iron therapy result in AGE (advanced glycation end-product), ALE (advanced lipoxidation end-product) and AOPP (advanced oxidation protein product) formation, favouring together with elevated CRP (C-reactive protein) levels the development of cardiovascular and cerebrovascular complications. Enhanced plasma levels of homocysteine and ADMA (asymmetric dimethylarginine) contribute to this process. In addition, in chronic renal insufficiency hyperphosphatemia and an enhanced calcium x phosphorus ion product are associated with the morbidity and mortality of the patients, particularly in the presence of fetuin deficiency. Phosphorus, AGEs and AOPPs, beside other factors, catalyze the conversion of vascular smooth muscle cells to osteoblast--like cells (particularly in the presence of monocytes/macrophages), resulting in bone matrix protein formation. Other risk factors, such as age, male sex, smoking, hypertension, diabetes, chronic inflammation, insulin resistance or dyslipidemia (enhanced non-HDL-cholesterol) also contribute to the atherosclerotic risk profile of the patient with chronic renal insufficiency. While there is growing understanding of the mechanisms involved in arteriosclerosis, atherosclerosis and vascular calcification in uremia, we are still missing effective therapeutic maneuvers for reduction of excess mortality in uremic patients.

Arginine↗
PubMed2003

Hyperphosphataemia and treatment with sevelamer in haemodialysis patients.

More than 60% of patients on chronic haemodialysis (HD) have a serum phosphate level above 5.5 mg/dl (1.75 mmol/l), which recently has been recommended as an appropriate target in patients with end-stage renal disease (ESRD). Preventing hyperphosphataemia and elevated Ca x P product not only ameliorates the progression of secondary hyperparathyroidism and bone disease, but also appears to reduce cardio-vascular morbidity and mortality from vascular calcifications. Dietary phosphate restriction and the administration of aluminium and calcium salts have been the principal means of phosphate control over the last decade. Unfortunately, the protean disturbances of toxic aluminium accumulation in the body virtually eliminated aluminium from clinical practice. Calcium-based therapy, although well tolerated, results in frequent hypercalcaemia when administered concurrently with vitamin D analogues, despite a decrease in the concentration of dialysate calcium. Sevelamer (Renagel((R))) has been a novel, non-absorbable calcium- and aluminium-free synthetic polymer. In initial studies, sevelamer reduced serum phosphate, Ca x P product and parathyroid hormone (PTH) in a manner comparable with calcium acetate therapy. However, the effect on PTH levels may prove to be inconsistent. It seems somewhat less effective in binding phosphate than aluminium, although no direct comparisons have been made. In a recent study, it attenuated the progression of vascular calcification in HD patients. It also binds bile acids, resulting in substantially lower low-density lipo-protein cholesterol levels. The major obstacle to its current use is a substantial increase in the cost associated with sevelamer therapy.

Epoxy Compounds↗
PubMed2006

Successful management of critical limb ischemia with intravenous sodium thiosulfate in a chronic hemodialysis patient.

Vascular calcification is common among hemodialysis (HD) patients and contributes to the development of peripheral arterial disease. A 57-year-old Japanese man who had been on HD for 30 years was referred to us for severe pain with multiple ulcers on his toes and fingers. He was an ex-smoker and had no diabetes mellitus. On admission, he had ulcers on his big toes bilaterally and right 2nd - 4th fingers. Peripheral pulses were strong and his ankle-brachial pressure index was above 1.3. Laboratory data were as follows: calcium 9.9 mg/dl, albumin 3.3 g/dl, phosphate 3.0 mg/dl, Ca x P product 30, and parathyroid hormone 98 pg/ml. He had a parathyroidectomy in 1998 and 1999. X-rays of his hands and legs showed diffuse subcutaneous arteriolar calcification. Angiography revealed no local stenotic lesions. Despite intensive therapies including hyperbaric oxygen therapy, painful gangrene developed on his right big toe and the pain was so intense that he could not go to sleep in a supine position. We infused intravenous sodium thiosulfate (20 g) 3 times weekly, based on previous reports. Within 4 - 5 days, he experienced rapid and dramatic symptom relief. The score of the visual analogue pain scale improved from 10/10 - 2/10. The signs of ischemia, measured by transcutaneous partial oxygen pressure and thermography, improved significantly. During the infusion of sodium thiosulfate, the patient complained of nausea, vomiting and hyperosmia. These adverse symptoms were resolved after discontinuation of the infusion. Pain relief was sustained and he could walk after 2 weeks of infusion. Our case supports the use of sodium thiosulfate as a novel therapeutic choice for critical limb ischemia with severe vascular calcification in chronic HD patients.

Calcinosis↗
PubMed2006

Function and effect of bone morphogenetic protein-7 in kidney bone and the bone-vascular links in chronic kidney disease.

In two independent and separate studies, we have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreased the serum phosphate. In the first study, the serum Ca PO(4), parathyroid hormone (PTH), and calcitriol were maintained normal after renal ablation in mice, and even mild renal injury equivalent to stage 3 CKD decreased bone formation rates. More recently, these observations were rediscovered in low-density lipoprotein receptor null (LDLR-/-) mice fed high-fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidemia and insulin resistance). We demonstrated that these mice have vascular calcification (VC) of both the intimal atherosclerotic type and medial calcification. We have also shown that VC is made worse by CKD and ameliorated by bone morphogenetic protein-7 (BMP-7). The finding that high-fat fed LDLR-/- animals with CKD had hyperphosphatemia which was prevented in BMP-7-treated animals lead us to examine the skeletons of these mice. It was found that significant reductions in bone formation rates were associated with high-fat feeding, and superimposing CKD resulted in the adynamic bone disorder (ABD), while VC was made worse. The effect of CKD to decrease skeletal anabolism (decreased bone formation rates and reduced number of bone modelling units) occurred despite secondary hyperparathyroidism. The BMP-7 treatment corrected the ABD and hyperphosphatemia, owing to BMP-7-driven stimulation of skeletal phosphate deposition reducing plasma phosphate and thereby removing a major stimulus to VC. A pathological link between abnormal bone mineralization and VC through the serum phosphorus was demonstrated by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. Thus, in the metabolic syndrome with CKD, a reduction in bone forming potential of osteogenic cells leads to the ABD producing hyperphosphatemia and VC, processes ameliorated by BMP-7, in part through increased bone formation and skeletal deposition of phosphate and in part through direct actions on vascular smooth muscle cells. We have demonstrated that the processes leading to vascular calcification begin with even mild levels of renal injury affecting the skeleton before demonstrable hyperphosphatemia and that they are preventable and treatable. Therefore, early intervention in the skeletal disorder associated with CKD is warranted and may affect mortality of the disease.

Animals↗
PubMed2004

Association of alpha2-HS glycoprotein (AHSG, fetuin-A) polymorphism with AHSG and phosphate serum levels.

Alpha2-HS glycoprotein (AHSG), also known as fetuin-A, is a plasma protein displaying high-affinity interaction with calcium phosphate, by which ectopic vascular calcification is prevented. This investigation has attempted to evaluate the relationship between AHSG polymorphism and serum levels of AHSG and calcium-related parameters. AHSG levels in unrelated individuals were measured by quantitative rocket immunoelectrophoresis and were 581+/-38, 542+/-31, and 494+/-23 mg/l for three major genotypes of AHSG1 homozygotes (n=99), heterozygotes (n=55), and AHSG2 homozygotes (n=22), respectively (differences were significant: P<0.001). The circulating AHSG level was therefore influenced by the genetic polymorphism with the additive reduction in the AHSG2 allele. Statistical analysis of simple and multiple regression models revealed no associations between AHSG levels and serum values of total calcium, albumin-corrected total calcium, and ionized calcium. However, the AHSG levels demonstrated a significant negative correlation with free phosphate levels (P<0.001), indicating that AHSG is a novel determinant of serum phosphate. The AHSG polymorphism is attributable to the hereditary variation of AHSG and phosphate serum levels, which may affect skeletal development and chronic disorders such as vascular calcification.

Adult↗
PubMed2001

Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women.

Osteoprotegerin (OPG) and its ligand are cytokines that regulate osteoclastogenesis and that may be involved in the regulation of vascular calcification. We examined whether serum OPG levels were associated with stroke, mortality, and cardiovascular risk factors, including diabetes, as well as with bone mineral density and fractures in a sample of 490 participants in a prospective cohort of white women, at least 65 yr of age. We found that OPG levels, assayed blinded from serum obtained at baseline, were about 30% greater in women with diabetes (mean +/- SD, 0.30 +/- 0.17 ng/mL) than in those without diabetes (0.23 +/- 0.10 ng/mL; P = 0.0001). OPG levels were associated with all-cause mortality [age-adjusted odds ratio, 1.4/SD (0.11 ng/mL) increase in serum OPG level; 95% confidence interval, 1.2--1.8] and cardiovascular mortality (odds ratio, 1.4; 95% confidence interval, 1.1--1.8); these effects were not confounded by diabetes. OPG levels were not associated with baseline bone mineral density or with subsequent strokes or fractures. The association of serum OPG levels with diabetes and with cardiovascular mortality raises the possibility that OPG may be a cause of or a marker for vascular calcification.

Aged↗
PubMed2005

Calcium, phosphorus and vitamin D disorders in uremia.

BACKGROUND: Alterations in calcium, phosphate (P) and vitamin D metabolism play a critical role in the development of secondary hyperparathyroidism (SH), parathyroid hyperplasia and soft tissue and vascular calcification. METHODOLOGY: Studies were performed in uremic dogs and rats fed a low and high P diet over a period of 1-4 months. In addition, in vitro studies were performed in normal parathyroid glands incubated in culture media containing 0.2 mM P (low) or 2.0 mM P (high). RESULTS: Uremic rats maintained on a low P diet did not develop SH or parathyroid hyperplasia. There was an enhancement of p21, the suppressor of the cell cycle, in these parathyroid glands. Opposite results were obtained using a high P diet. There was an enhancement of transforming growth factor-alpha and epidermal growth factor receptor, known enhancers of cell proliferation. In vitro studies demonstrated the direct effect of P on parathyroid hormone secretion. CONCLUSIONS: Early dietary P restriction prevents the development of SH and parathyroid hyperplasia. If dietary P restriction is applied to rats with established SH, there is a significant amelioration of SH and parathyroid hyperplasia. In addition, control of serum P in uremic patients is crucial in the prevention of vascular calcification.

Animals↗
PubMed2006

Fetuin-A and kidney function in persons with coronary artery disease--data from the Heart and Soul Study.

BACKGROUND: Fetuin-A is a serum protein that inhibits ectopic vascular calcification and is present in lower concentrations in end-stage renal disease than in healthy controls. Whether fetuin-A concentrations are also lower in the setting of mild-to-moderate chronic kidney disease (CKD) is unknown. METHODS: We evaluated the associations of several parameters of kidney function including measured 24 h urinary creatinine clearance (CrCl), estimated glomerular filtration rate (GFR) by the Mayo Clinic quadratic GFR equation (qGFR), serum cystatin-C concentrations, and urinary albumin-to-creatinine ratio with serum fetuin-A concentrations in 970 outpatients with coronary artery disease. We used general linear models to determine the adjusted mean fetuin-A concentrations within each kidney function category. RESULTS: The mean age of the study sample was 67 years, 82% were male, 71% had hypertension and 26% had diabetes mellitus. In adjusted analysis, we observed no significant differences in mean fetuin-A concentrations across groups defined by CrCl, qGFR, or albumin-to-creatinine ratio groups. For example, adjusted mean fetuin-A concentrations were 0.66 g/l in participants with CrCl > 90, 60-90 and 45-60 ml/min/1.73 m(2), and 0.65 g/l in participants with CrCl < 45 ml/min/1.73 m(2). Higher serum cystatin-C (indicating worse kidney function) was associated with higher adjusted mean serum fetuin-A concentrations (lowest quartile 0.62 g/l, highest quartile 0.68 g/l; P for trend <0.001). CONCLUSIONS: Among ambulatory patients with coronary artery disease, there is no evidence that mild-to-moderate CKD is associated with lower concentrations of serum fetuin-A compared with persons with normal renal function. The mechanisms explaining the association between CKD and vascular calcification remain elusive.

Aged↗
PubMed2005

Length of interdialytic interval influences serum calcium and phosphorus concentrations.

BACKGROUND: Higher levels of serum phosphorus and calcium are associated with increased haemodialysis (HD) patient mortality. Both of these factors act synergistically to promote vascular smooth muscle differentiation to an osteoblast-like phenotype and subsequent vascular calcification. The aim of this study was to investigate the influence of interdialytic interval on serum levels, as well as the influence of oral calcium-based phosphate binder load on the magnitude of the observed differences. METHODS: We studied 100 patients undergoing HD three times per week, over a 2 week period. Haemoglobin, albumin, calcium and phosphate were measured pre-dialysis before each HD session. Oral phosphate binder usage was recorded. All patients were treated with dialysate containing 1.25 mEq/l calcium. RESULTS: Both mean serum phosphate and calcium were higher after the long interdialytic interval (1.59+/-0.05 vs 1.45+/-0.04 mmol/l, P = 0.0005, and 2.46+/-0.03 vs 2.4+/-0.02 mmol/l, P = 0.001, for serum phosphate and uncorrected calcium, respectively). There were no significant differences in haemoglobin or serum albumin, indicating that variable dilution from an increased hydration status in the long interdialytic interval was unlikely to contribute to these observed differences. A total of 74 patients were treated with calcium-containing binders and 26 patients with sevelamer. Patients on sevelamer did not exhibit the observed cyclical increase in serum calcium seen in patients on calcium-containing binders (mean difference in serum calcium 0.09+/-0.01 mmol/l in the calcium-treated group vs 0.01+/-0.01 mmol/l in the sevelamer-treated patients, P = 0.0004). The increase in serum calcium after the long interval as compared with the short interval was proportional to the daily amount of the oral calcium-containing binder load ingested (r = 0.63, P<0.0001). CONCLUSION: Cyclical differences in interdialytic interval and overall exposure to both dietary phosphate and oral calcium load influence serum levels. This may have consequences for registry reporting, therapy modulation and potentially the pathogenesis of accelerated vascular calcification seen in HD patients.

Calcium↗
PubMed2001

Total chemical synthesis of human matrix Gla protein.

Human matrix Gla protein (MGP) is a vitamin K-dependent extracellular matrix protein that binds Ca2+ ions and that is involved in the prevention of vascular calcification. MGP is a 10.6-kD protein (84 amino acids) containing five gamma-carboxyglutamic acid (Gla) residues and one disulfide bond. Studies of the mechanism by which MGP prevents calcification of the arterial media are hampered by the low solubility of the protein (<10 microg/mL). Because of solubility problems, processing of a recombinantly expressed MGP-fusion protein chimera to obtain MGP was unsuccessful. Here we describe the total chemical synthesis of MGP by tBoc solid-phase peptide synthesis (SPPS) and native chemical ligation. Peptide Tyr1-Ala53 was synthesized on a derivatized resin yielding a C-terminal thioester group. Peptide Cys54-Lys84 was synthesized on Lys-PAM resin yielding a C-terminal carboxylic acid. Subsequent native chemical ligation of the two peptides resulted in the formation of a native peptide bond between Ala53 and Cys54. Folding of the 1-84-polypeptide chain in 3 M guanidine (pH 8) resulted in a decrease of molecular mass from 10,605 to 10,603 (ESI-MS), representing the loss of two protons because of the formation of the Cys54-Cys60 internal disulfide bond. Like native MGP, synthetic MGP had the same low solubility when brought into aqueous buffer solutions with physiological salt concentrations, confirming its native like structure. However, the solubility of MGP markedly increased in borate buffer at pH 7.4 in the absence of sodium chloride. Ca2+-binding to MGP was confirmed by analytical HPLC, on which the retention time of MGP was reduced in the presence of CaCl2. Circular dichroism studies revealed a sharp increase in alpha-helicity at 0.2 mM CaCl2 that may explain the Ca2+-dependent shift in high-pressure liquid chromatography (HPLC)-retention time of MGP. In conclusion, facile and efficient chemical synthesis in combination with native chemical ligation yielded MGP preparations that can aid in unraveling the mechanism by which MGP prevents vascular calcification.

Blotting, Western↗