The vitamin D status of a general adult urban population was estimated between November and April in 1569 subjects selected from 20 French cities grouped in nine geographical regions (between latitude 43 degrees and 51 degrees N). Major differences in 25-hydroxyvitamin D (25(OH)D) concentration were found between regions, the lowest values being seen in the North and the greatest in the South, with a significant 'sun' effect (r = 0.72; p = 0.03) and latitude effect (r = -0.79; p = 0.01). In this healthy adult population, 14% of subjects exhibited 25(OH)D values < or = 30 nmol/l (12 ng/ml), which represents the lower limit (< 2 SD) for a normal adult population measured in winter with the same method (RIA Incstar). A significant negative correlation was found between serum intact parathyroid hormone (iPTH) and serum 25(OH)D values (p < 0.01). Serum iPTH held a stable plateau level at 36 pg/ml as long as serum 25(OH)D values were higher than 78 nmol/l (31 ng/ml), but increased when the serum 25(OH)D value fell below this. When the 25(OH)D concentration became equal to or lower than 11.3 nmol/l (4.6 ng/ml), the PTH values reached the upper limit of normal values (55 pg/ml) found in vitamin D replete subjects. These results showed that in French normal adults living in an urban environment with a lack of direct exposure to sunshine, diet failed to provide an adequate amount of vitamin D. It is important to pay attention to this rather high prevalence of vitamin D insufficiency in the general adult population and to discuss the clinical utility of winter supplementation with low doses of vitamin D.

BACKGROUND

Alpha-Klotho (alphaKl) regulates mineral metabolism such as calcium ion (Ca(2+)) and inorganic phosphate (Pi) in circulation. Defects in mice result in clinical features resembling disorders found in human aging. Although the importance of transmembrane-type alphaKl has been demonstrated, less is known regarding the physiological importance of soluble-type alphaKl (salphaKl) in circulation.

OBJECTIVE

The aims of this study were: (1) to establish a sandwich ELISA system enabling detection of circulating serum salphaKl, and (2) to determine reference values for salphaKl serum levels and relationship to indices of renal function, mineral metabolism, age and sex in healthy subjects.

RESULTS

We successively developed an ELISA to measure serum salphaKl in healthy volunteers (n=142, males 66) of ages (61.1+/-18.5year). The levels (mean+/-SD) in these healthy control adults were as follows: total calcium (Ca; 9.46+/-0.41mg/dL), Pi (3.63+/-0.51mg/dL), blood urea nitrogen (BUN; 15.7+/-4.3mg/dL), creatinine (Cre; 0.69+/-0.14mg/dL), 1,25 dihydroxyvitamin D (1,25(OH)(2)D; 54.8+/-17.7pg/mL), intact parathyroid hormone (iPTH; 49.2+/-20.6pg/mL), calcitonin (26.0+/-12.3pg/mL) and intact fibroblast growth factor (FGF23; 43.8+/-17.6pg/mL). Serum levels of salphaKl ranged from 239 to 1266pg/mL (mean+/-SD; 562+/-146pg/mL) in normal adults. Although salphaKl levels were not modified by gender or indices of mineral metabolism, salphaKl levels were inversely related to Cre and age. However, salphaKl levels in normal children (n=39, males 23, mean+/-SD; 7.1+/-4.8years) were significantly higher (mean+/-SD; 952+/-282pg/mL) than those in adults (mean+/-SD; 562+/-146, P<0.001). A multivariate linear regression analysis including children and adults in this study demonstrated that salphaKl correlated negatively with age and Ca, and positively with Pi. Finally, we measured a serum salphaKl from a patient with severe tumoral calcinosis derived from a homozygous missense mutation of alpha-klotho gene. In this patient, salphaKl level was notably lower than those of age-matched controls.

CONCLUSIONS

We established a detection system to measure human serum salphaKl for the first time. Age, Ca and Pi seem to influence serum salphaKl levels in a normal population. This detection system should be an excellent tool for investigating salphaKl functions in mineral metabolism.

Low 25-hydroxyvitamin D (25[OH] D) results in hyperparathyroidism and is among the endocrine derangements of adult obesity. There are differing recommendations on defining low 25(OH) D: hypovitaminosis D (serum 25[OH] D concentration <75 nmol/L) and vitamin D deficiency (serum 25[OH] D concentration <50 nmol/L). We sought to evaluate the prevalence of low levels of 25(OH) D by examining hypovitaminosis D (<75 nmol/L), vitamin D sufficiency >> or =75 nmol/L), vitamin D insufficiency (50-74.9 nmol/L), and vitamin D deficiency (<50 nmol/L) in pediatric obesity and the relationship to other calciotropic hormones and adiposity. Serum 25(OH) D, intact parathyroid hormone (iPTH), ionized calcium, glucose, and insulin levels along with hemoglobin A(1c) (HbA(1c)) and quantitative insulin sensitivity check index (QUICKI) were determined in 127 subjects aged 13.0 +/- 3.0 years (49 Caucasian [C], 39 Hispanic [H], and 39 African American [AA]; 61.2% female; body mass index 36.4 +/- 8.1 kg/m(2)) during fall/winter (F/W) and spring/summer (S/S). Body composition was determined by bioelectrical impedance. Hypovitaminosis D was present in 74% of the cohort, but was more prevalent in the H (76.9%, P < .05) and AA (87.2%, P < .05) groups than in the C group (59.1%). Hypovitaminosis D corresponded to decreased vitamin D intake (P < .005) and was more prevalent in F/W than S/S (98.4% vs 49.2, P < .01). Vitamin D deficiency was identified in 32.3% of the entire cohort and was more prevalent in the H (43.6%, P < .0001) and AA (48.7%, P < .0001) groups than in the C group (10.2%) associated with decreased vitamin D intake (P < .0001). Vitamin D insufficiency was present in 41.7% of the cohort, with similar prevalence among C (48.9%), H (33.3%), and AA (38.5%). Vitamin D insufficiency corresponded to decreased vitamin D intake (P < .005), with similar prevalence in F/W and S/S (45.3% vs 38.1%), whereas vitamin D deficiency was not only accompanied by decreased vitamin D intake (P < .0001) but was more prevalent in F/W than S/S (53.1% vs 11.1%, P < .0001). Serum 25(OH) D and iPTH (r = -0.41, P < .0001) levels were negatively correlated without seasonal and ethnic/racial influences. Hypovitaminosis D and vitamin D-deficient groups had higher body mass index, fat mass (FM), and iPTH, but had lower QUICKI than vitamin D-sufficient group (P < .01). Whereas FM was negatively correlated with 25(OH) D (r = -0.40, P < .0001), it was positively correlated with iPTH (r = 0.46, P < .0001) without seasonal and racial/ethnic influences. Serum 25(OH) D was also positively correlated with QUICKI (r = 0.24, P < .01), but was inversely correlated with HbA(1c) (r = -0.23, P < .01). Hypovitaminosis D was identified in 74% of obese subjects, whereas vitamin D deficiency was observed in 32.3% of our cohort. Vitamin D status was influenced by vitamin D intake, season, ethnicity/race, and adiposity. Interrelationships between 25(OH) D, iPTH, and FM were not influenced by season and race/ethnicity. Furthermore, serum 25(OH) D was positively correlated with insulin sensitivity, which was FM mediated, but negatively correlated with HbA(1c), implying that obese children and adolescents with low vitamin D status may be at increased risk of developing impaired glucose metabolism independent of body adiposity. Additional studies are needed to evaluate the underlying mechanisms.

BACKGROUND

Proteinuria is a marker of cardiovascular and renal disease in patients with chronic kidney disease (CKD), and reduction in proteinuria has been associated with improved cardiovascular and renal outcomes. While active vitamin D and its analogs have been shown to have renal protective effects in animals, these hormones have not been shown to reduce proteinuria in CKD patients.

METHODS

In three double-blind, randomized, placebo-controlled studies to evaluate the safety and efficacy of oral paricalcitol, 220 CKD stage 3 and 4 patients with secondary hyperparathyroidism (SHPT) were randomized to oral paricalcitol (N= 107, mean dose 9.5 microg/week) or placebo (N= 113) and followed for up to 24 weeks. In conjunction with other safety measures, proteinuria was measured by dipstick and read by an automated reader at the beginning and end of trial. We subsequently analyzed the dipstick data to evaluate the effect of paricalcitol on proteinuria.

RESULTS

At baseline, proteinuria was present in 57 patients randomized to oral paricalcitol and 61 patients randomized to placebo (NS). At the final visit, 29/57 (51%) of the paricalcitol patients compared to 15/61 (25%) placebo patients had reduction in proteinuria, P= 0.004 (odds for reduction in proteinuria 3.2 times greater for paricalcitol patients, 95% CI 1.5-6.9). For the patients who had both proteinuria at baseline and parathyroid hormone (PTH) suppression (end point defined as 2 consecutive>> or =30% decreases in iPTH from baseline), 27/51 (53%) patients had a reduction in the proteinuria in the paricalcitol group and 0/7 (0%) had a reduction in proteinuria in the placebo group. Reduction of proteinuria favored patients on paricalcitol, regardless of age, sex, race, diabetes mellitus, hypertension, or use of therapies to block the renin-angiotensin-aldosterone system (RAAS).

CONCLUSIONS

Our results demonstrate that the reduction in proteinuria was associated with paricalcitol treatment, and the reduction in proteinuria was independent of concomitant use of agents that block the RAAS. Paricalcitol as a potential pharmacologic means of reducing proteinuria in CKD patients warrants further investigation.

A new radioimmunoassay for human parathyroid hormone (PTH) in serum, which can measure the hormone present in 94% of the normal sera tested, is described. It is based on the ability of human PTH to compete with (131)I-labeled bovine PTH for binding to an antiserum directed against porcine PTH. This antiserum distinguishes between human PTH extracted from parathyroid adenomata and that present in hyperparathyroid sera. Evidence is given to suggest that this is due to immunochemical changes in the hormone extracted from adenomata and not to immunochemical heterogeneity of the hormone present in serum. Physiologic data supporting the validity and specificity of the assay are presented. Induced episodes of hypercalcemia and hypocalcemia resulted in appropriate responses in serum immunoreactive PTH (IPTH) in normal subjects and in patients with Paget's disease of bone. In normals, there was a progressive increase in serum IPTH in the late afternoon and evening, suggesting a diurnal secretory rhythm. A negative correlation was found between the serum calcium and serum IPTH over the normal range of serum calcium values; a positive correlation was found between these variables in patients with primary hyperparathyroidism. There was apparent overlap between serum IPTH values in normal subjects and patients with primary hyperparathyroidism, but formal discriminate analysis of values for serum calcium and IPTH demonstrated separation of these two groups, without overlap.

BACKGROUND

A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative.

METHODS

The association between the markers of mineral and bone disease and clinical outcomes was examined in 7970 patients treated in European Fresenius Medical Care facilities over a median of 21 months. Baseline and time-dependent (TD) Cox regression were performed using Kidney Disease Outcomes Quality Initiative (KDOQI) target ranges as reference categories, adjusting for demographics, medical history, dialysis parameters, inflammation, medications and laboratory parameters. Fractional polynomial (FP) models were also used.

RESULTS

Hazard ratio (HR) estimates from baseline analysis for iPTH were U-shaped [>600 pg/mL, HR = 2.10, 95% confidence interval (CI) 1.62-2.73; <75 pg/mL, HR = 1.46, 95% CI 1.17-1.83]. TD analysis confirmed the results for iPTH. Baseline analysis showed that calcium >2.75 mmol/L increased risk of death (HR = 1.70, 95% CI 1.19-2.42). TD analysis showed that both low (HR = 1.19, 95% CI 1.04-1.37) and high calcium (HR = 1.74, 95% CI 1.30-2.34) increased risk of death. Baseline analysis for phosphate showed a U-shaped pattern (<1.13 mmol/L, HR = 1.18, 95% CI 1.01-1.37; >1.78 mmol/L, HR = 1.32, 95% CI 1.13-1.55). TD analysis confirmed the results for phosphate <1.13 mmol/L. HR estimates were higher in patients with diabetes versus those without diabetes for baseline analysis only (P-value = 0.014). FP analysis confirmed the results of baseline and TD analyses.

CONCLUSIONS

Patients with iPTH, calcium and phosphate levels within the KDOQI target ranges have the lowest risk of mortality compared with those outside the target ranges.

Management of secondary hyperparathyroidism is challenging with traditional therapy. The calcimimetic cinacalcet HCl acts on the calcium-sensing receptor to increase its sensitivity to calcium, thereby reducing parathyroid hormone (PTH) secretion. This phase 3, multicenter, randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of cinacalcet in hemodialysis (HD) and peritoneal dialysis (PD) patients with PTH>> or =300 pg/ml despite traditional therapy. A total of 395 patients received once-daily oral cinacalcet (260 HD, 34 PD) or placebo (89 HD, 12 PD) titrated from 30 to 180 mg to achieve a target intact PTH (iPTH) level of < or =250 pg/ml. During a 10-wk efficacy assessment phase, cinacalcet was more effective than control for PTH reduction outcomes, including proportion of patients with mean iPTH levels < or =300 pg/ml (46 versus 9%), proportion of patients with>> or =30% reduction in iPTH from baseline (65 versus 13%), and proportion of patients with>> or =20,>> or =40, or>> or =50% reduction from baseline. Cinacalcet had comparable efficacy in HD and PD patients; 50% of PD patients achieved a mean iPTH < or =300 pg/ml. Cinacalcet also significantly reduced serum calcium, phosphorus, and Ca x P levels compared with control treatment. The most common side effects, nausea and vomiting, were usually mild to moderate in severity and transient. Once-daily oral cinacalcet was effective in rapidly and safely reducing PTH, Ca x P, calcium, and phosphorus levels in patients who received HD or PD. Cinacalcet offers a new therapeutic option for controlling secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.

BACKGROUND

Coronary artery calcification (CAC) correlates with the extent of coronary atherosclerosis and, consequently, with an increased risk for cardiovascular events. CAC is more frequent in uremic patients than in the general population. Nearly all data about CAC relate to patients on dialysis therapy. This study evaluates the prevalence and extent of CAC in patients with chronic renal failure (CRF) not yet on dialysis therapy.

METHODS

Consecutive outpatients with CRF not on dialysis therapy were enrolled and compared with controls (ie, healthy volunteers and patients with essential hypertension with normal renal function). Patients and controls were asymptomatic and had no previous history of myocardial infarction, coronary bypass surgery, or angioplasty. Patients with diabetes were excluded. Clinical characteristics, biochemical test results (included homocysteinemia and C-reactive protein level), and serum concentrations of calcium, phosphorus, and intact parathyroid hormone (iPTH) were evaluated in patients and controls. CACs were searched for and scored by means of spiral computed tomography (CT). To assess the CAC progression rate, spiral CT was repeated in some patients.

RESULTS

Eighty-five patients and 55 controls were studied. Patients were aged 52 +/- 13 years and had a CRF duration of 6.3 +/- 5.6 years, glomerular filtration rate of 33.0 +/- 16.0 mL/min (0.55 +/- 0.27 mL/s), serum calcium level of 9.5 +/- 0.5 mg/dL (2.37 +/- 0.12 mmol/L), serum phosphorus level of 4.1 +/- 0.9 mg/dL (1.32 +/- 0.29 mmol/L), and serum iPTH level of 143 +/- 121 pg/mL (ng/L). CAC was found in 40% of patients and 13% of controls; calcification scores were 422 +/- 634 in patients and 43.9 +/- 33 in controls. Only age ( P < 0.001) was a predictor of CAC. In patients with a repeated score performed (after a mean of 7.9 months), calcification scores increased (from 383 +/- 627 to 682 +/- 890) in 8 of 10 patients.

CONCLUSIONS

CAC is already present in the early phase of CRF; the prevalence is greater in patients with CRF than in controls, but less than that reported in dialysis patients. Serum concentrations of calcium, phosphorus, iPTH, and inflammation markers do not predict the appearance or progression of CAC.

Serum fibroblast growth factor 23 (FGF23) is a novel phosphaturic factor and important for the regulation of inorganic phosphate (Pi) homeostasis. In this study, we examined an acute effect of oral Pi loading on serum FGF23 levels to clarify the role in rapid adjustment of serum Pi level. We performed a randomized, double-blind, crossover study in eight healthy male volunteers. The subjects were alternately served one of three test meals containing different Pi amounts (400 mg (P400), 800 mg (P800), and 1200 mg (P1200)) as lunch at noon. The postprandial changes in serum levels of Pi, Ca, 1,25-dihydroxyvitamin D, intact-parathyroid hormone (iPTH), intact-FGF23 (iFGF23), and urinary excretion of Pi and Ca until 8 h after Pi loading were estimated. Serum Pi levels and urinary Pi excretion significantly increased within 1 h after P400 and P800 intake. Serum iPTH levels at 1-2 and 4-6 h after P1200 intake was significantly higher than those of P400 intake. Serum iFGF23 levels slightly decreased up to 8 h after P400 intake and up to 6 h after P800 intake, but not changed in P1200 intake. Significant increase of iFGF23 was observed at 8 h after P1200 intake compared with both P400 and P800 intake. Additionally, negative association was detected between iFGF23 and serum Pi, whereas positive association was observed between iPTH and serum Pi during the short period. We conclude that oral Pi loading cannot rapidly increase serum FGF23 level. FGF23 may be not associated with rapid adaptation of Pi homeostasis.

BACKGROUND

The quick parathyroid hormone assay (QPTH) reliably measures intact parathyroid hormone (iPTH) levels intraoperatively. The accuracy in predicting postoperative calcemia is related to blood sample timing and the criteria applied. To improve specificity or to decrease the cost of QPTH, several criteria have been used to predict complete excision. This study compares the Miami criterion with other published QPTH criteria in predicting operative outcome.

METHODS

QPTH and the Miami criterion (iPTH drop>> or =50% from the highest of either preincision or pre-excision level at 10 minutes after gland excision), were used to predict postoperative calcium levels of 341 consecutive patients with sporadic primary hyperparathyroidism who were followed>> or =6 months after the operation or recognized as operative failures. Intraoperative iPTH values of these patients were reanalyzed with the use of 5 published criteria to predict complete resection. Postoperative calcium levels were correlated with criteria predictions.

RESULTS

Miami criterion correctly predicted postoperative calcium levels in 329 of 341 patients and was incorrect in 12 (3 false positives, 9 false negatives). With the use of other criteria, 2 of the 3 false-positive results would be prevented, but the 3% rate of false-negative predictions would increase to between 6% and 24%, causing unnecessary neck explorations to search for multiglandular disease.

CONCLUSIONS

Surgeons trying to increase QPTH specificity significantly decrease the accuracy and intraoperative usefulness of the assay. The Miami criterion has the highest accuracy when compared with other criteria.

BACKGROUND

Dialysis Outcomes and Practice Patterns Study has shown that the proportion of haemodialysis patients with adequate mineral metabolism parameters according to the Kidney Disease Outcome Quality Initiative (K/DOQI) guidelines is very low. The adequacy of such parameters in relation to the recommended ranges in patients with different chronic kidney disease (CKD) stages has not been reported. The objective of this study is to provide an in-depth description of mineral metabolism in the early stages of CKD in a European population, and to compare it with current recommendations for stages 3-5 (K/DOQI guidelines).

METHODS

A total of 1836 patients were classified into stages 1-5 according to K/DOQI guidelines. The following clinical and biochemical data were recorded: age, gender, CKD aetiology, presence of diabetes, serum creatinine, creatinine clearance, serum phosphate, calcium, CaxP product and intact parathyroid hormone (PTH).

RESULTS

A decrease in 1,25-dihydroxyvitamin D and an increase in PTH are the earliest mineral metabolism alterations in CKD, while serum calcium and phosphate are altered later in the course of CKD. The percentages of patients with serum levels within the recommended K/DOQI guidelines for stages 3, 4 and 5 were as follows: serum calcium: 90.7, 85.6 and 55; serum phosphate: 90.9, 77.1 and 70.3; iPTH 42.4, 24.6 and 46.8 and Ca x P product 99.9, 99.6 and 83.8, respectively. The percentages of patients who had all four parameters within the recommended ranges were 34.9, 18.4 and 21.6 for stages 3, 4 and 5, respectively.

CONCLUSIONS

Mineral metabolism disturbances start early in the course of CKD. The first alterations to take place are a 1,25-dihydroxyvitamin D decrease, a 24 h urine phosphate decrease and a PTH elevation, which show significant level variation when the glomerular filtration rate falls below 60 ml/min. K/DOQI recommended levels for mineral metabolism parameters are difficult to accomplish, in particular for PTH levels.

BACKGROUND

Although bone disease is well described among end-stage renal disease (ESRD) patients, little attention has been paid to the occurrence of fracture. We sought to identify factors that are associated with hip fracture among ESRD patients.

METHODS

Data from patients who participated in the United States Renal Data System Dialysis Morbidity and Mortality Study Wave 1 were used for this study. Hip fractures occurring among these patients between 1993 and 1996 were identified from Medicare claims data available from the United States Renal Data System. Cox proportional hazards models were used to estimate the risk of hip fracture associated with demographic and medical variables.

RESULTS

Of the 4952 patients included in this analysis, 103 sustained a hip fracture. In the multivariate analysis, age (per increasing decade, RR = 1.40, 95% CI 1.20, 1.64), female gender (RR = 2.26, 95% CI 1.48, 3.44), race (blacks compared with whites, RR = 0.58, 95% CI 0.37, 0.91), body mass index (per 1 unit increase, RR 0.89, 95% CI 0.86, 0.93), and the presence of peripheral vascular disease (RR 1.94, 95% CI 1.29, 2.92) were independently associated with hip fracture. Serum intact parathyroid hormone (iPTH), aluminum, diabetes, and bicarbonate levels did not appreciably influence the risk of hip fracture.

CONCLUSIONS

Demographic and other characteristics that predict risk of hip fracture in the population at large also do so in ESRD patients. However, we could identify no characteristics of ESRD or its treatment that were independently related to hip fracture incidence.

The separate and combined effects of intermittent parathyroid hormone (iPTH) (1-34) and mechanical loading were assessed at trabecular and cortical sites of mouse long bones. Female C57BL/6 mice from 13 to 19 weeks of age were given daily injections of vehicle or PTH (1-34) at low (20 microg/kg/day), medium (40 microg/kg/day) or high (80 microg/kg/day) dose. For three alternate days per week during the last two weeks of this treatment, the tibiae and ulnae on one side were subjected to a single period of non-invasive, dynamic axial loading (40 cycles at 10 Hz with 10-second intervals between each cycle). Two levels of peak load were used; one sufficient to engender an osteogenic response, and the other insufficient to do so. The whole tibiae and ulnae were analyzed post-mortem by micro-computed tomography with a resolution of 5 microm. Treatment with iPTH (1-34) modified bone structure in a dose- and time-dependent manner, which was particularly evident in the trabecular region of the proximal tibia. In the tibia, loading at a level sufficient by itself to stimulate osteogenesis produced an osteogenic response in the low-dose iPTH (1-34)-treated trabecular bone and in the proximal and middle cortical bone treated with all doses of iPTH (1-34). In the ulna, loading at a level that did not by itself stimulate osteogenesis was osteogenic at the distal site when combined with high-dose iPTH (1-34). At both levels of loading, there were synergistic effects in cortical bone volume of the proximal tibia and distal ulna between loading and high-dose iPTH (1-34). Images of fluorescently labelled bones confirmed that such synergism resulted from increases in both endosteal and periosteal bone formation. No woven bone was induced by iPTH (1-34) or either level of loading alone, whereas the combination of iPTH (1-34) and the "sufficient" level of loading stimulated woven bone formation on endosteal and periosteal surfaces of the proximal cortex in the tibiae. Together, these data suggest that in female C57BL/6 mice, under some but not all circumstances, mechanical loading exerts an osteogenic response with iPTH (1-34) in trabecular and cortical bone.

BACKGROUND

Vitamin D deficiency leads to secondary hyperparathyroidism, which has a negative effect on bone metabolism in the elderly. Puberty is an important time of bone metabolism and growth. The effect of serum 25-hydroxyvitamin D [25(OH)D] concentrations on parathyroid hormone concentrations and bone mineral density (BMD) has not been well studied cross-sectionally in adolescents.

OBJECTIVE

We studied the effect of vitamin D status on serum intact parathyroid hormone (iPTH) concentrations and bone metabolism in adolescents.

METHODS

One hundred seventy-eight healthy female adolescents (aged 14-16 y) volunteered for this study, which was conducted in Finland (Helsinki, 60 degrees N) during the winter. Forearm BMD at radial and ulnar sites was measured by dual energy X-ray absorptiometry. The determinants of different variables were studied by use of regression models.

RESULTS

On the basis of the relation between serum 25(OH)D and iPTH concentrations, serum 25(OH)D concentrations>> approximately 40 nmol/L were needed to keep serum iPTH concentrations low. One hundred ten subjects (61.8%) had serum 25(OH)D concentrations < or =40 nmol/L. Twenty-four subjects (13.5%) were considered vitamin D deficient when the serum 25(OH)D concentration of 25 nmol/L was used as a cutoff. Subjects with serum 25(OH)D concentrations < or =40 nmol/L had low mean forearm BMD values at both the radial (P = 0.04) and ulnar (P = 0.08) sites.

CONCLUSIONS

A large percentage of adolescent females have low vitamin D status during the winter in Finland, which seems to have negative effects on bone health.

Cardiovascular disease is increasingly recognized as a life-limiting problem in young patients with chronic kidney disease, but there are few studies in children that describe its determinants. We studied the association of intact parathyroid hormone (iPTH) levels and their management on vascular structure and function in 85 children, ages 5-18 years, who had received dialysis for>> or =6 months. Compared to controls, dialysis patients had increased carotid intima-media thickness and pulse-wave velocity. All vascular measures positively correlated with serum phosphorus levels, while carotid intima-media thickness and cardiac calcification score also correlated with iPTH levels. Patients with mean time-integrated iPTH levels less than twice the upper limit of normal (n = 41) had vascular measures that were comparable to age-matched controls, but those with iPTH levels greater than twice the upper limit of normal (n = 44) had greater carotid intima-media thickness, stiffer vessels, and increased cardiac calcification than controls. Patients with increased carotid intima-media thickness had stiffer vessels and a greater prevalence of cardiac calcification. There was a strong dose-dependent correlation between vitamin D and all vascular measures, and calcium intake from phosphate binders weakly correlated with carotid intima-media thickness. In conclusion, both iPTH level and dosage of vitamin D are associated with vascular damage and calcification in children on dialysis.

Hypocalcaemia is a well-recognized manifestation of magnesium deficiency. We have studied seventeen patients with this syndrome in an attempt to determine the pathogenesis of the hypocalcaemia. Mean initial serum calcium concentration was 5-6 mg/dl and mean initial serum magnesium concentration was 0-75 mg/dl. Serum immunoreactive parathyroid hormone (IPTH) was measured in sixteen patients in the untreated state. Despite severe hypocalcaemia, serum IPTH was either undetectable (less than 150 pg/ml) or normal (less than 550 pg/ml) in all but two patients. Serial measurements made during the initial 4 days of magnesium therapy in four patients showed an increase in serum IPTH within 24h, but a delayed increase in serum calcium, which required approximately 4 days to reach normal values. The effect of the rapid normalization of serum magnesium on serum IPTH and serum calcium concentration was studied in three patients. Within 1 min after 144-300 mg of elemental magnesium was administered i.v., serum IPTH had risen from undetectable to 3600 pg/ml and 1725 pg/ml in two patients and from 425 pg/ml to 937 pg/ml in the third. Serum calcium concentrations were unchanged after 30-60 min. These data provide evidence for impaired parathyroid gland function in most of the magnesium deficient patients. The rapidity with which serum IPTH rose in response to magnesium therapy indicates that this may reflect a defect in parathyroid hormone (PTH) secretion rather than its biosynthesis. The failure of serum calcium concentration to increase during the initial days of magnesium repletion, at a time when serum IPTH concentrations were normal or elevated, suggests end-organ resistance to PTH in these patients. The renal response to PTH was examined in two magnesium deficient patients by measurement of urinary cyclic AMP excretion following administration of parathyroid extract. In both patients there was a minimal increase in urinary cyclic AMP concentrations. In contrast, when the hepatic response to glucagon was tested on the same patients by measurement of plasma cyclic AMP concentrations following administration of glucagon, normal increases were observed. These results suggest that adenylate cyclase systems of various organs may be affected differentially by a state of magnesium deficiency. It is suggested that magnesium deficiency may result in defective cyclic AMP generation in the parathyroid glands and in the PTH target organs. This could be the principal mechanism operative in both impaired PTH secretion and end-organ resistance to PTH which together contribute to the development of hypocalcaemia.

OBJECTIVE

To identify a relation between loss of muscle strength and vitamin D deficiency in ambulatory elderly persons not receiving vitamin D supplementation.

METHODS

Cross-sectional study.

METHODS

All measurements were taken at the Department of Geriatrics, University Hospital, Basel, Switzerland.

METHODS

Three hundred nineteen patients (103 women, 216 men) selected by random sampling from participants in an ongoing interdisciplinary study on aging (mean age for women, 74.2 yrs; for men, 76.7 yrs).

METHODS

Leg extension power (LEP) and body mass index (BMI); serum values of 25-hydroxyvitamin D [calcidiol, 25(OH)D], 1,25-hydroxyvitamin D [calcitriol, 1,25(OH)2D], and intact parathyroid hormone (iPHT).

RESULTS

Twelve percent of women and 18% of men had 25(OH)D values below the normal range (<12 ng/mL). Muscle strength was lower in older subjects (female: r = -.35; p = .0005/male: r = -.48; p < .0001) and was lower in women than in men (p < .0001). In men both 25(OH)D and 1,25(OH)2D was significantly correlated with LEP (r = 0.24; p = .0004/r = .14; p = .045). In women, only 1,25(OH)2D was significantly correlated with LEP (r = 0.22; p = .034). In an ANCOVA including all participants and explaining LEP by sex, age, BMI, 1,25(OH)2D, 25(OH)D, and iPTH, all factors showed significant effects except 25(OH)D and iPTH (r2 = .41).

CONCLUSIONS

Muscle strength declined with age in ambulatory elderly people and showed modest, but significant, positive correlation with 1,25(OH)2 vitamin D in both sexes and with 25(OH)D in male subjects. Therefore vitamin D deficiency appears to contribute to the age-related loss of muscle strength, which might be more pronounced in institutionalized elderly people with a high prevalence of vitamin D deficiency.

BACKGROUND

Bariatric surgery has been proven the most effective treatment of morbid obesity, but micronutrient deficiency following bariatric surgery is a major concern. Increasing evidence points to a generally poor micronutrient status in obese subjects.

METHODS

We assessed micronutrient status in 232 morbidly obese subjects (BMI>> or = 35 kg/m(2)) prior to bariatric surgery. Serum albumin, calcium, phosphate, magnesium, ferritin, hemoglobin, zinc, folate, vitamin B(12), 25-OH vitamin D(3), and intact parathormone (iPTH) were determined. In a sub-sample of 89 subjects, we additionally assessed copper, selenium, vitamin B(1), B(3), B(6), A, and E levels.

RESULTS

Deficiencies were found in 12.5% of the subjects for albumin, 8.0% for phosphate, 4.7% for magnesium, 6.9% for ferritin, 6.9% for hemoglobin, 24.6% for zinc, 3.4% for folate, and 18.1% for vitamin B(12). In addition, 25.4% showed a severe 25-OH vitamin D(3) deficiency, which was accompanied by a secondary hyperparathyroidism in 36.6% cases. Prevalence of albumin deficiency (p < 0.007) and of anemia (p < 0.003; in women only) significantly increased with BMI. Of note, 48.7% of the subjects showed at least one of the most prevalent deficiencies, i.e., vitamin B(12), zinc and severe 25-OH vitamin D(3) deficiency. In the sub-sample, 32.6% showed a selenium, 5.6% a vitamin B(3), 2.2% a vitamin B(6), and 2.2% a vitamin E deficiency. Copper, vitamin B(1), and vitamin A deficiency was found in none of the subjects.

CONCLUSIONS

Data indicate a high prevalence of micronutrient deficiencies in morbidly obese subjects. Based on these results, we strongly recommend a systematic assessment of the micronutrient status in all candidates for bariatric surgery.

BACKGROUND

Very few studies have evaluated both parathyroid hormone (PTH) and 25-hydroxyvitamin D [25(OH)D] and their effects on bone mass in children.

OBJECTIVE

We studied the associations of serum 25(OH)D and intact PTH (iPTH) with bone mineral content (BMC) and bone mineral density (BMD) at different bone sites and the relation between serum 25(OH)D and iPTH in early pubertal and prepubertal Finnish girls.

METHODS

The subjects were 10-12-y-old girls (n = 193) at Tanner stage 1 or 2, who reported a mean (+/- SD) dietary calcium intake of 733 +/- 288 mg/d. 25(OH)D, iPTH, tartrate-resistant acid phosphatase 5b (TRAP 5b), urinary calcium excretion, BMC, areal BMD, and volumetric BMD were assessed by using different methods.

RESULTS

Thirty-two percent of the girls were vitamin D deficient [serum 25(OH)D < or = 25 nmol/L], and 46% of the girls had an insufficient concentration (26-40 nmol/L). iPTH and TRAP 5b concentrations were significantly higher in the deficient group than in the insufficient and sufficient groups [iPTH: 43.9 +/- 15.7 compared with 38.6 +/- 11.2 pg/L (P = 0.049) and 32.7 +/- 12.1 pg/L (P < 0.001), respectively; TRAP 5b: 12.2 +/- 2.9 compared with 11.0 +/- 2.8 U/L (P = 0.009) and 10.9 +/- 1.9 U/L (P = 0.006), respectively]. The girls in the deficient group also had significantly lower cortical volumetric BMD of the distal radius (P < 0.001) and tibia shaft (P = 0.002). High iPTH concentrations were also associated with low total-body apparent mineral density and urinary calcium excretion (P < 0.007).

CONCLUSIONS

Vitamin D-deficient girls have low cortical BMD and high iPTH concentrations, which are consistent with secondary hyperparathyroidism. A low vitamin D concentration accompanied by high bone resorption (TRAP 5b) may limit the accretion of bone mass in young girls.

Current literature suggests associations between abnormal mineral metabolism (MM) to cardiovascular disease in dialysis populations, with conflicting results. MM physiology is complex; therefore, it was hypothesized that constellations of MM parameters, reflecting this complexity, would be predictive of mortality and that this effect would be modified by dialysis duration (DD). Prevalent dialysis patients in British Columbia, Canada, who had measurements of calcium (Ca), phosphate (Pi), and parathyroid hormone (iPTH) between January and March 2000 were followed prospectively until December 2002. Statistical analysis included Cox proportional hazard models with Ca, Pi, and iPTH alone and in combination as explanatory variables; analyses were stratified by DD. The 515 patients included in this analysis represent British Columbia and Canadian dialysis populations: 69% were on hemodialysis, mean age was 60 +/- 17 yr, 40% were female, and 34% had diabetes. Mean Ca and Pi values were 2.32 +/- 0.22 mmol/L and 1.68 +/- 0.59 mmol/L, respectively, and median iPTH was 15.8 pmol/L (25th to 75th percentile: 6.9 to 37.3 pmol/L). Serum Pi, after adjusting for demographic, dialysis type and adequacy, hemoglobin, and albumin, independently predicted mortality (risk ratio [RR], 1.56 per 1 mmol/L; 95% confidence interval [CI], 1.15 to 2.12; P = 0.004). When combinations of parameters were modeled (overall P = 0.003), the combinations of high serum Pi and Ca with high iPTH (RR, 3.71; 95% CI, 1.53 to 9.03; P = 0.004) and low iPTH (RR, 4.30; 95% CI, 2.01 to 9.22; P < 0.001) had highest risks for mortality as compared with the combination of high iPTH with normal serum Ca and Pi that had the lowest mortality and was used as index category. These effects varied across different strata of DD. This analysis demonstrates the importance of examining combinations of MM parameters as opposed to single variables alone and the effect of DD. In so doing, the complex interaction of time and MM can begin to be understand. Further exploration is required.

BACKGROUND

Circulating 25 hydroxyvitamin D (25 (OH)D), an accurate measure of vitamin D status, is markedly greater in individuals with increased exposure to ultraviolet B (UVB) light via sunlight or the use of artificial UV light. Aside from the known relationship between vitamin D and bone, vitamin D has also been implicated in immune function and inflammation. Furthermore, a mass of evidence is accumulating that vitamin D deficiency could lead to immune malfunction. Our overall objective was to study the relationship between vitamin D status (as determined by serum 25(OH) D concentrations) and inflammatory markers in healthy women.

METHODS

This observational study included 69 healthy women, age 25-82 years. Women with high UVB exposure and women with minimal UVB exposure were specifically recruited to obtain a wide-range of serum 25(OH)D concentrations. Health, sun exposure and habitual dietary intake information were obtained from all subjects. Body composition was determined by dual-energy-x-ray absorptiometry. A fasting blood sample was collected in the morning and analyzed for serum 25(OH)D, parathyroid hormone (iPTH), estradiol (E2), cortisol, and inflammatory markers [tumor necrosis factor -alpha (TNF-alpha), interleukin-6 and -10 (IL-6, IL-10), and C-reactive protein (CRP)].

RESULTS

Women with regular UVB exposure (Hi-D) had serum 25(OH)D concentrations that were significantly higher (p < 0.0001) and iPTH concentrations that were significantly lower (p < 0.0001) than women without regular UVB exposure (Lo-D). Although IL-6, IL-10, and CRP did not have a statistically significant relationship with 25(OH)D concentrations, linear regression models revealed a significant inverse relationship between serum 25(OH)D and TNF-alpha concentrations. This relationship remained significant after controlling for potential covariates such as body fat mass, menopausal status, age, or hormonal contraceptive use.

CONCLUSIONS

Serum 25(OH)D status is inversely related to TNF-alpha concentrations in healthy women, which may in part explain this vitamin's role in the prevention and treatment of inflammatory diseases. Results gleaned from this investigation also support the need to re-examine the biological basis for determining optimal vitamin D status.

BACKGROUND

The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQItrade mark) has established guidelines for treatment of secondary hyperparathyroidism (HPT). The ability of cinacalcet HCl (Sensipartrade mark) treatment to improve achievement of target levels of parathyroid hormone (PTH), calcium, phosphorus, and calcium-phosphorus product (Ca x P) was investigated in subjects on dialysis with secondary HPT.

METHODS

Data were combined from three placebo-controlled, double-blind, 26-week studies with similar design that randomized 1136 subjects on dialysis to receive traditional therapy plus cinacalcet or placebo. Oral cinacalcet was titrated from 30 to 180 mg/day. Achievement of K/DOQI goals was determined for each treatment group overall and for subgroups defined by baseline intact PTH (iPTH) and Ca x P levels.

RESULTS

Cinacalcet-treated subjects were more likely to achieve a mean <em>iPTH</em> </=300 pg/mL (31.8 pmol/L) than were control subjects on traditional therapy (56% vs. 10%, P < 0.001). Cinacalcet-treated subjects were more likely to achieve concentrations of serum calcium within 8.4 to 9.5 mg/dL (2.10-2.37 mmol/L) and serum phosphorus within 3.5 to 5.5 mg/dL (1.13-1.78 mmol/L) than were control subjects (49% vs. 24% and 46% vs. 33%, P < 0.001 for each). Cinacalcet also improved achievement of Ca x P < 55 mg(2)/dL(2) (4.44 mmol(2)/L(2)) and concurrent achievement of Ca x P < 55 mg(2)/dL(2) (4.44 mmol(2)/L(2)) and <em>iPTH</em> </=300 pg/mL (31.8 pmol/L) (65% vs. 36% and 41% vs. 6%, P < 0.001 for each).

CONCLUSIONS

In subjects on dialysis with secondary HPT, cinacalcet facilitates achievement of the K/DOQI-recommended targets for PTH, calcium, phosphorus, and Ca x P.

Paricalcitol (19-nor-1alpha-25-dihydroxyvitamin D2), a new vitamin D analog developed for the treatment of secondary hyperparathyroidism, was evaluated in three double-blind, placebo-controlled, dose-escalating, randomized multicenter trials. A total of 78 patients (40 Paricalcitol injection, 38 placebo) achieved treatment phase eligibility, which included intact parathyroid hormone (iPTH)>> or = 400 pg/ml, normalized serum calcium levels between 8.0 and 10.0 mg/dl, and calcium x phosphorus product values less than 75. Study end points included a decrease in iPTH of at least 30% or a maximum of five dose escalations. After a 4-wk washout, paricalcitol or placebo was administered intravenously three times per week after dialysis for 12 wk. Study drug was started at a dose of 0.04 microg/kg and was increased by 0.04 microg/kg every 2 wk to a maximal allowable dose of 0.24 microg/kg or until at least a 30% decrease in serum iPTH was achieved. The dose of paricalcitol that decreased iPTH by at least 30% became the maintenance dose. Of 40 patients receiving paricalcitol, 27 (68%) had at least a 30% decrease in serum iPTH for 4 consecutive weeks, compared with three of 38 patients (8%) receiving placebo (P < 0.001). For patients who received 12 wk of treatment with paricalcitol, the levels of iPTH decreased significantly from 795+/-86 to 406+/-106 pg/ml (P < 0.001), whereas the values for PTH were 679+/-41 pg/ml before and 592+/-41 pg/ml after 12 wk of therapy in patients receiving placebo (P=NS). Also, there was a significant difference between treatment groups for the change from baseline PTH levels (P < 0.001). Paricalcitol treatment resulted in a significant reduction in serum alkaline phosphatase from 148+/-23 U/L to 101+/-14 U/L (P < 0.001) in patients treated for 12 wk compared with 120+/-9 U/L to 130+/-11 U/L (P=NS) in patients receiving placebo for 12 wk. Importantly, hypercalcemia did not occur before achieving target serum iPTH levels in any of the paricalcitol-treated patients. There was no significant difference for the change from baseline in serum phosphorus within or between treatment groups. There was no significant difference in adverse events between the paricalcitol and placebo-treated groups. These studies demonstrate that paricalcitol safely and effectively suppresses iPTH levels in hemodialysis patients. This second generation vitamin D analog may have a wider therapeutic window than current vitamin D preparations, and thus may allow reduction in PTH with less hypercalcemia.

OBJECTIVE

Our goal was to compare direct quantitation of circulating free 25-hydroxyvitamin D (25(OH)D)levels to calculated free 25(OH)D levels and their relationships to intact PTH (iPTH), a biomarker of 25(OH)D effect, in humans with a range of clinical conditions.

METHODS

Serum samples and clinical data were collected from 155 people: 111 without cirrhosis or pregnancy (comparison group), 24 cirrhotic patients with albumin <2.9 g/dL, and 20 pregnant women (second and third trimester). Total 25(OH)D (LC/MS/MS), free 25(OH)D (immunoassay), vitamin D binding protein (DBP) (immunoassay), albumin, and iPTH (immunoassay) were measured.

RESULTS

Total 25(OH)D, DBP, and albumin were lowest in patients with cirrhosis, but measured free 25(OH)D was highest in this group (P < .001). DBP was highest in pregnant women (P < .001), but measured free 25(OH)D did not differ from the comparison group. Calculated free 25(OH)D was positively correlated with measured free 25(OH)D (P < .0001) but explained only 13% of the variability with calculated values higher than measured. African Americans had lower DBP than other ethnic populations within all clinical groups (P < .03), and differences between measured and calculated free 25(OH)D were greatest in African Americans (P < .001). Measured free 25(OH)D was correlated with total 25(OH)D (P < .0001; r(2) = 0.51), but calculated free 25(OH)D was not. Similarly, both measured free 25(OH)D (P < .02) and total 25(OH)D (P < .05) were correlated with iPTH, but calculated free 25(OH)D was not.

CONCLUSIONS

Calculated free 25(OH)D levels varied considerably from direct measurements of free 25(OH)D with discrepancies greatest in the data for African Americans. Differences in DBP binding affinity likely contributed to estimation errors between the races. Directly measured free 25(OH)D concentrations were related to iPTH, but calculated estimates were not. Current algorithms to calculate free 25(OH)D may not be accurate. Further evaluation of directly measured free 25(OH)D levels to determine its role in research and clinical management of patients is needed.