BACKGROUND

25-Hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) have been shown to correlate with several markers of metabolic syndrome in adult populations. We evaluated the relationship between circulating intact parathyroid hormone (iPTH) and 25(OH)D and indices of metabolic syndrome in obese adolescents.

METHODS

Body mass index (BMI), body composition, 25(OH)D, iPTH, fasting lipids, glucose, high-sensitivity C-reactive protein (hsCRP), glycosylated hemoglobin (HbA1c), insulin, and the homeostatic model assessment for insulin resistance (HOMA-IR) were evaluated in 133 obese adolescents.

RESULTS

Vitamin D deficiency [25(OH)D <50 nmol/L] was present in 45.1% of all patients, with higher prevalence in African-American (AA) and Hispanic (H) than Caucasian (C) subgroups (63.9% and 56.4% vs. 25.9%; P<0.001). iPTH and 25(OH)D were inversely correlated (r=-0.75; P<0.0001), with AA displaying a higher iPTH: 25(OH)D ratio than H and C subgroups (P<0.05). Whereas fat mass (FM) was negatively correlated with 25(OH)D (r=-0.30; p<0.001), it was positively correlated with iPTH levels (r=0.38; P<0.0001). Metabolic syndrome was identified in 57.9% of the cohort with higher iPTH, iPTH:25(OH)D ratio, but lower 25(OH)D than participants without metabolic syndrome (P<0.02). Whereas iPTH showed main effects for hsCRP (β=0.24, t=2.61, P<0.05) and triglycerides:high-density lipoprotein cholesterol (TG:HDL-C) (β=0.21, t=2.13, p<0.05), independent of serum 25(OH)D, it did not reveal a main effect for HOMA-IR.

CONCLUSIONS

Metabolic syndrome is associated with a higher iPTH:25(OH)D ratio than those without metabolic syndrome, implying greater risk of cardiovascular morbidities among AA subjects than other ethnic groups. Furthermore, the serum iPTH level is a predictor of chronic inflammation and dyslipidemia, independent of 25(OH)D.

BACKGROUND

The Vitamin D Receptor gene (VDR) is expressed in many tissues and modulates the expression of several other genes. The purpose of this study was to investigate the association between metabolic syndrome (MetSyn) with the presence of VDR 2228570 C>> T and VDR 1544410 A>> G polymorphisms in Brazilian adults.

METHODS

Two hundred forty three (243) individuals were included in a cross-sectional study. MetSyn was classified using the criteria proposed by National Cholesterol Educational Program--Adult Treatment Panel III. Insulin resistance and β cell secretion were estimated by the mathematical models of HOMA IR and β, respectively. The VDR 2228570 C>> T and VDR 1544410 A>> G polymorphisms were detected by enzymatic digestion and confirmed by allele specific PCR or amplification of refractory mutation.

RESULTS

Individuals with MetSyn and heterozygosis for VDR 2228570 C>> T have higher concentrations of iPTH and HOMA β than those without this polymorphism, and subjects with recessive homozygosis for the same polymorphisms presented higher insulin resistance than those with the heterozygous genotype. There is no association among VDR 1544410 A>> G and components of MetSyn, HOMA IR and β, serum vitamin D (25(OH)D₃) and intact parathormone (iPTH) levels in patients with MetSyn. A significant lower concentration of 25(OH)D₃ was observed only in individuals without MetSyn in the VDR 1544410 A>> G genotype. Additionally, individuals without MetSyn and heterozygosis for VDR 2228570 C>> T presented higher concentration of triglycerides and lower HDL than those without this polymorphism.

CONCLUSIONS

Using two common VDR polymorphism data suggests they may influence insulin secretion, insulin resistance an serum HDL-cholesterol in our highly heterogeneous population. Whether VDR polymorphism may influence the severity of MetSyn component disorder, warrants examination in larger cohorts used for genome-wide association studies.

BACKGROUND

Magnesium salts bind dietary phosphorus, but their use in renal patients is limited due to their potential for causing side effects. The aim of this study was to evaluate the efficacy and safety of magnesium carbonate (MgCO(3)) as a phosphate-binder in hemodialysis patients.

METHODS

Forty-six stable hemodialysis patients were randomly allocated to receive either MgCO(3) (n=25) or calcium carbonate (CaCO(3)), (n=21) for 6 months. The concentration of Mg in the dialysate bath was 0.30 mmol/l in the MgCO(3) group and 0.48 mmol/l in the CaCO(3) group.

RESULTS

Only two of 25 patients (8%) discontinued ingestion of MgCO(3) due to complications: one (4%) because of persistent diarrhea, and the other (4%) because of recurrent hypermagnesemia. In the MgCO(3) and CaCO(3) groups, respectively, time-averaged (months 1-6) serum concentrations were: phosphate (P), 5.47 vs. 5.29 mg/dl, P=ns; Ca, 9.13 vs. 9.60 mg/dl, P<0.001; Ca x P product, 50.35 vs. 50.70 (mg/dl)(2), P=ns; Mg, 2.57 vs. 2.41 mg/dl, P=ns; intact parathyroid hormone (iPTH), 285 vs. 235 pg/ml, P<0.01. At month 6, iPTH levels did not differ between groups: 251 vs. 212 pg/ml, P=ns. At month 6 the percentages of patients with serum levels of phosphate, Ca x P product and iPTH that fell within the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines were similar in both groups, whereas more patients in the MgCO(3) group (17/23; 73.91%) than in the CaCO(3) group (5/20, 25%) had serum Ca levels that fell within these guidelines, with the difference being significant at P<0.01.

CONCLUSIONS

Our study shows that MgCO(3) administered for a period of 6 months is an effective and inexpensive agent to control serum phosphate levels in hemodialysis patients. The administration of MgCO(3) in combination with a low dialysate Mg concentration avoids the risk of severe hypermagnesemia.

OBJECTIVE

The impact of different dialysis modalities on oxidative stress and inflammation and the factors implicated in this interrelationship have not been adequately studied. This study was designed to comparatively evaluate the effect of hemodialysis (HD) and peritoneal dialysis (PD) on oxidative stress and inflammatory biomarkers and to search for associated factors.

METHODS

We studied 20 HD, 11 PD patients and 11 healthy controls. Calculations were based on total antioxidant capacity (TAC) and superoxide dismutase (SOD), by spectrophotometry, as oxidative stress biomarkers; and high sensitivity CRP (hs-CRP), Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-alpha), by ELISA, as inflammation biomarkers.

RESULTS

HD and PD patients showed significantly increased levels of TA C, SOD and hs-CRP compared to healthy controls. No significant difference was observed in TNF-alpha and IL-6. Compared to HD patients, PD patients showed TNF-alpha levels that were increased, although non-significantly, and significantly higher homocysteine (Hcy). No differences were observed for IL-6, hs-CRP, TA C and SOD. In HD patients, significant positive correlations were found between intact parathyroid hormone (iPTH) and TNF-alpha, and between uric acid (UA) and TAC. Beta2-microglobulin (Beta2M) was negatively correlated with TAC, total cholesterol (TC) positively with TNF-alpha and negatively with SOD, and triglycerides (TG) correlated positively with TNF-alpha. In PD patients, TG correlated positively with TNF-alpha, HDL-cholesterol negatively with TNF-alpha, LDL-cholesterol negatively with SOD, and Beta2M negatively with SOD.

CONCLUSIONS

HD and PD patients show similar degrees of inflammation and oxidative stress activation. Factors such as UA, iPTH, Beta2M and lipid profile correlate to oxidative stress and inflammatory biomarkers in both HD and PD patients.

OBJECTIVE

African-Americans (AA) with normal renal function have higher parathyroid hormone (PTH) levels than Caucasians (C). This difference was also noted in cross-sectional studies of patients on dialysis. In this study, we evaluated patients with end-stage renal disease who have just began dialysis and who were not receiving any vitamin D therapy.

METHODS

A total of 363 patients were recruited (C: 260; AA: 103). All patients had serum calcium, phosphorus, alkaline phosphatase and intact PTH (iPTH) levels measured within 3 months of initiating dialysis.

RESULTS

Serum PTH levels were significantly higher in AA vs. C (383 +/- 33 vs. 246 +/- 19, p < 0.001). This difference was present despite similar calcium, phosphorus and alkaline phosphatase levels between the 2 groups and regardless of gender or diabetes status. However, PTH levels in patients younger than 47 years of age were similar in both groups.

CONCLUSIONS

PTH levels in ESRD patients over 47 years of age are higher in AA compared to C. The difference is, in part, due to an age-dependent reduction in PTH seen only in C. Further studies are needed to understand the mechanisms of these racial differences and to verify whether they mirror similar alterations at the level of the end-organ tissue.

BACKGROUND

The available literature is still controversial and shows that surgical (parathyroidectomy, PTX) or medical (calcitriol) treatment actually improved or even corrected the rhEPO-resistant anemia of ESRD patients with severe SHP. The aims of this study were to 1) assess the influence of SHP on hematological parameters in ESRD patients, 2) evaluate whether or not calcitriol could improve anemia and reduce the need of erythropoietin in dialysis patients, and 3) investigate the longitudinal effect of a parathyroidectomy for 6 months on regarding any improvements in calcitriol-refractory ESRD patients.

METHODS

37 chronic hemodialysis patients in Chang Gung Memorial Hospital Dialysis Unit were divided into two groups: patients with SHP (iPTH)300 pg/mL) and patients without SHP (ipTH<300 pg/mL) before calcitriol therapy was applied. Sixteen patients remain with a status of hyperparathyroidism and were considered candidates for calcitriol therapy. Furthermore, we divided the patients according to the response of HPT to calcitriol into responding patients and nonresponding patients. Among nonresponder groups, three patients agreed to accept surgical intervention to treat their hyperparathyroidism status.

RESULTS

The phosphate levels and serum alkaline phosphatase levels in patients with SHP were significantly higher when compared with those without SHP (P<0.05). As for the hematological data, hematocrit for patients with SHP was significantly higher than those without SHP (10.5 +/- 0.6 vs. 8.9 +/- 0.8, p<0.05). Other hematological parameters such as transferrin saturation and serum ferritin were not significantly different. We found a significant difference in alkaline phosphate levels in responding and nonresponding patients at 6 months on calcitriol therapy. Concomitantly, the hematocrit level is significantly higher in responding group when compared to those in nonresponding group (10.63 +/- 0.72 vs. 8.96 +/- 1.21, p<0.01). As for the dose of EPO requirement, significant difference between groups was also found after 6-month treatment (3617 +/- 2011 vs. 5416 +/- 1947, p<0.05). As for rhEPO dose requirement, positive effects of PTX were significantly found. The rhEPO doses needed to maintain patients in the hematocrit target range of 30-33% decreased gradually by 29% from 5323 +/- 1326 micro to 3774 +/- 2145 micro per week. The hematocrit level showed a significant increase at 3 months after PTX (p<0.05). This effect lasted until 6 months after PTX. The serum ferritin level was constantly around 350 to 400 pg/mL. While the transferrin saturation decreased 3 months after PTX (p<0.05) and recovered at 6 months.

CONCLUSIONS

ESRD patients with SHP, usually associated with more severe anemia show resistance to rhEPO. In this case, investigation of SHP is strongly recommended with measurement of serum PTH, phosphate and alkaline phosphatase level. Treatment of calcitriol has a beneficial effect on renal anemia in ESRD patients with SHP. In addition, PTX could also provide another choosing therapy in improving renal anemia when medical treatment fails.

BACKGROUND

Though spondyloarthropathy has been described in patients with sporadic idiopathic hypoparathyroidism (SIH), the clinical profile is not known.

OBJECTIVE

To describe the clinical profile including radiological features of spondyloarthropathy and prevalence of HLA-B27 allele in patients with hypoparathyroidism, and to identify any differences from ankylosing spondylitis.

METHODS

Clinical characteristics and radiographs of pelvis and spine were assessed in 40 consecutive patients with SIH. Radiographs were assessed by radiologist (RS) and rheumatologist (RG) for the features of spondyloarthropathy including sacroiliitis, syndesmophytes and hip joint calcification, and so on. HLA-B27 genotyping was carried out in patients with SIH, and 195 healthy controls using duplex PCR. Fourteen control radiographs were from age-matched normal individuals.

RESULTS

Three patients with SIH had clinically overt spondyloarthropathy which closely resembled ankylosing spondylitis. Fourteen (eight females and six males) of the 40 patients with SIH showed radiological changes including syndesmophytes in lower dorsal or dorso-lumbar spine (n = 6), sacroiliitis and new bone formation at the acetabular rim of the hip joint (n = 10). Though all six patients demonstrating syndesmophytes had new bone formation at hip, sacroiliitis was seen in only three of them. None of the 14 controls had syndesmophytes, sacroiliitis or hip joint calcification. The mean (SD) duration of illness (15.4 +/- 8.7 vs. 6.5 +/- 5.9 years, P < 0.01), BMI (24.1 +/- 5.2 vs. 20.8 +/- 3.7 kg/m(2), P = 0.04) and frequency of basal ganglia calcification was higher (100%vs. 57.7%, P < 0.01) in patients who showed changes of spondyloarthropathy in comparison to those without these changes. On multiple logistic regression analysis, only duration of hypoparathyroid illness was associated with spondyloarthropathy with an odds ratio of 1.17 (95% CI = 1.05-1.30, P < 0.01) per year increase in the duration. The mean age, serum total calcium, inorganic phosphorus and serum intact PTH (iPTH) levels were not significantly different between SIH patients with and without spondyloarthropathy. The frequency of HLA-B27 allele was comparable between SIH and the control groups.

CONCLUSIONS

Thus, spondyloarthropathy is a distinct clinical entity in patients with SIH. Its salient clinical features include presence of syndesmophytes at the thoracic or thoraco-lumbar spine, mild sacroiliitis, calcification at the acetabular margin of hip, preserved bone density, equal distribution in both sexes and lack of HLA-B27 association. Presence of spondyloarthropathy, like basal ganglia calcification, is associated with longer duration of hypoparathyroidism. It is important to differentiate hypoparathyroid-related spondyloarthropathy from ankylosing spondylitis because the management for the two disorders is different.

BACKGROUND

Mineral and bone disorder (MBD) in patients with chronic kidney disease is associated with increased morbidity and mortality. Studies regarding the status of MBD treatment in developing countries, especially in Chinese dialysis patients are extremely limited.

METHODS

A cross-sectional study of 1711 haemodialysis (HD) patients and 363 peritoneal dialysis (PD) patients were enrolled. Parameters related to MBD, including serum phosphorus (P), calcium (Ca), intact parathyroid hormone (iPTH) were analyzed. The achievement of MBD targets was compared with the results from the Dialysis Outcomes and Practice Study (DOPPS) 3 and DOPPS 4. Factors associated with hyperphosphatemia were examined.

RESULTS

Total 2074 dialysis patients from 28 hospitals were involved in this study. Only 38.5%, 39.6% and 26.6% of them met the Kidney Disease Outcomes Quality Initiative (K/DOQI) defined targets for serum P, Ca and iPTH levels. Serum P and Ca levels were statistically higher (P < 0.05) in the HD patients compared with those of PD patients, which was (6.3 ± 2.1) mg/dL vs (5.7 ± 2.0) mg/dL and (9.3 ± 1.1) mg/dL vs (9.2 ± 1.1) mg/dL, respectively. Serum iPTH level were statistically higher in the PD patients compared with those of HD patients (P = 0.03). The percentage of patients reached the K/DOQI targets for P (37.6% vs 49.8% vs 54.5%, P < 0.01), Ca (38.6% vs 50.4% vs 56.0%, P < 0.01) and iPTH (26.5% vs 31.4% vs 32.1%, P < 0.01) were lower among HD patients, compared with the data from DOPPS 3 and DOPPS 4. The percentage of patients with serum phosphorus level above 5.5 mg/dL was 57.4% in HD patients and 47.4% in PD patients. Age, dialysis patterns and region of residency were independently associated with hyperphosphatemia.

CONCLUSIONS

Status of MBD is sub-optimal among Chinese patients receiving dialysis. The issue of hyperphosphatemia is prominent and needs further attention.

BACKGROUND

Insufficient evidenced-based information is available for the treatment of osteoporosis in hemodialysis (HD) patients.

METHODS

In 102 HD patients, bone mineral density (BMD) was measured twice 16 ± 3 months apart. In the second BMD measurement 66 of them had a femoral neck (FN) T-score <-2.5. Of these 66 patients, 38 consented to a bone biopsy. Depending on both the bone biopsy findings and parathyroid hormone levels, patients were assigned to treatment groups. Eleven patients with osteitis fibrosa and iPTH >300 pg/ml received cinacalcet, 11 with osteitis fibrosa and iPTH <300 pg/ml received ibandronate, 9 with adynamic bone disease received teriparatide, and 7 with mild abnormalities received no treatment. A third BMD measurement was done after an average treatment period of 13-16 months. We compared the annual percent change of FN and lumbar spine (LS) BMD before and during treatment.

RESULTS

FN and LS BMD decreased significantly in the cinacalcet group, with an annual change of 3.6 and 3.4% before treatment to -4.2% (p = 0.04) and -7.7% (p = 0.02) during treatment, respectively. In the teriparatide group, FN and LS BMD increased, although not significantly, with an annual change of -5.4 and -2.6% before treatment to 2.7 and 4.9% during treatment, respectively. In both the ibandronate and the no treatment groups, BMD change rate remained negative during the whole study.

CONCLUSIONS

Teriparatide administration improved BMD in HD patients with adynamic bone disease, although these results did not reach statistical significance. In HD patients with osteitis fibrosa, ibandronate did not improve BMD while cinacalcet reduced BMD.

BACKGROUND

We previously reported on increased bone strontium (Sr) levels in dialysis patients with osteomalacia versus those presenting other types of renal osteodystrophy. A causal role of strontium in the development of osteomalacia was established in a chronic renal failure (CRF) rat model.

METHODS

In the present study we investigated whether the effect of Sr on bone was related to dosage. Four groups of CRF rats were studied: a control group (control-CFR; N=6) not receiving strontium and three groups of animals loaded orally with Sr during 18 weeks by adding the element as the SrCl2. H20 compound to the drinking water at concentrations of 0.03 g/100mL (Sr-30; N=6), 0.075 g/100mL (Sr-75; N=6), or 0.15 g/100mL (Sr-150; N=6) respectively. A fifth group consisting of seven animals with intact renal function (control-NRF), not receiving Sr served as controls for the effect of CRF on bone histology.

RESULTS

As compared to the control-NRF and control-CRF groups, Sr administration resulted in a dose-dependent increase in bone and serum Sr levels. No difference in body weight and biochemical serum and urinary parameters [i.e., calcium (Ca), phosphorus (P), and creatinine] was noted between the various CRF groups. At sacrifice, intact parathyroid hormone (iPTH) levels of CRF groups were significantly (P < 0.05) higher than the values measured in the control-NRF group indicating the development of hyperparathyroidism secondary to the installation of the CRF. This is further supported by the differences in bone histomorphometry between the control-CRF and control-NRF animals, which, respectively, showed an increased amount of osteoid (mean +/- SEM 3.4 +/- 1.2% vs. 0.37 +/- 0.14%, P < 0.05) in combination with a distinct osteoblastic activity (35 +/- 11% vs. <2%, P < 0.05) and an increased bone formation rate [(BFR), 677 +/- 177 microm 2/mm2/day vs. 130 +/- 50 microm 2/mm2/day, P < 0.05]. Bone surface area and erodic perimeter did not differ between the various study groups. In the Sr-30 group, Sr loading went along with a dramatic reduction of the BFR as indicated by the total absence of double tetracyclin labels and osteoblastic activity, which in the presence of a low to normal amount of osteoid (2.7 +/- 1.9%) points to the development of the adynamic type of renal osteodystrophy. Interestingly, compared to the control-CRF group, histodynamic and histologic parameters of the Sr-75 group did not differ significantly and a substantial osteoblastic activity (7.6 +/- 4.0%) was seen also. In the Sr-150 group, the various osteoid parameters were significantly (P < 0.05) increased vs. all other groups and were accompanied by a reduced BFR and mineral apposition rate (MAR) and an increased mineralization lag time (MLT), indicating a mineralization defect and the development of osteomalacia.

CONCLUSIONS

Our findings indicate that the role of Sr in the development of bone lesions in renal failure is complex and that, depending on the dose, the element may act via multiple pathways.

Controversy persists over: 1) how best to restore low serum 25-hydroxyvitamin D (25D) levels (vitamin D2 [D2] vs vitamin D3 [D3]); 2) how best to define vitamin D status (total [protein-bound + free] vs free 25D); and 3) how best to assess the bioactivity of free 25D.

To assess: 1) the effects of D2 vs D3 on serum total and free 25D; and 2) whether change in intact PTH (iPTH) is more strongly associated with change in total vs free 25D.

Participants previously enrolled in a D2 vs D3 trial were matched for age, body mass index, and race/ethnicity. Participants received 50 000 IU of D2 or D3 twice weekly for 5 weeks, followed by a 5-week equilibration period. Biochemical assessment was performed at baseline and at 10 weeks.

Thirty-eight adults (19 D2 and 19 D3) ≥18 years of age with baseline 25D levels <30 ng/mL were recruited from an academic ambulatory osteoporosis clinic.

Serum measures were total 25D, free 25D (directly measured), 1,25-dihydroxyvitamin D, calcium, and iPTH. Urine measure was fasting calcium:creatinine ratio.

Baseline total (22.2 ± 3.3 vs 23.3 ± 7.2 ng/mL; P = .5) and free (5.4 ± 0.8 vs 5.3 ± 1.7 pg/mL; P = .8) 25D levels were similar between D2 and D3 groups. Increases in total (+27.6 vs +12.2 ng/mL; P = .001) and free (+3.6 vs +6.2 pg/mL; P = .02) 25D levels were greater with D3 vs D2. Percentage change in iPTH was significantly associated with change in free (but not total) 25D, without and with adjustment for supplementation regimen, change in 1,25-dihydroxyvitamin D, and change in calcium.

D3 increased total and free 25D levels to a greater extent than D2. Free 25D may be superior to total 25D as a marker of vitamin D bioactivity.

Bone vessel functions during bone remodeling are poorly understood. They depend on both vessel network structure and vasomotor regulation. Parathyroid hormone (PTH) is a systemic vasodilator that may modulate microvascularization. Moreover, although intermittent PTH is anti-osteoporotic, continuous PTH administration can be catabolic for bone. Finally, ovariectomy (OVX) reduces bone perfusion and vessel density in mice. We reasoned that the effects of PTH on bone vascularization might depend on its administration regimen and be impacted by ovariectomy. A 100-µg/kg PTH 1-84 daily dose was administered for 15 days to 4-month-old female C57BL/6 mice, either as daily sc injection (iPTH) or continuously (cPTH; ALZET minipump). Blood pressure (BP) and tibia bone perfusion were measured in vivo with a laser Doppler device. Histomorphometry of bone and barium-contrasted vascular network were performed on the same tibia. Compared with untreated controls, both iPTH and cPTH increased bone formation but had opposite effects on resorption. Both iPTH and cPTH were slightly angiogenic. Intermittent PTH increased microvessel size (+48%, p < 0.001), whereas cPTH decreased it (-29%, p = 0.009). iPTH increased bone perfusion (27%, p < 0.001) with no change in BP, whereas cPTH did not. The vascular effects of a 15-day iPTH treatment were analyzed in OVX mice and compared with sham-operated and OVX untreated controls. Two other anti-osteoporotic drugs, zoledronate (one injection, 70 µg/kg) and propranolol, (5 mg/kg/d) were tested in OVX mice. Although no change in bone mass was observed, iPTH stimulated bone formation and prevented the OVX-induced reduction in bone perfusion and vessel density. Both zoledronate and propranolol strongly lowered bone turnover, but surprisingly, zoledronate prevented OVX-induced reduction in bone perfusion but propranolol did not. Our integrative approach thus demonstrates that the effects of PTH on bone vessel structure and function depend on its mode of administration as well as on the HPG-axis hormonal status, and that OVX-induced vascular changes are prevented by iPTH.

Cinacalcet, a novel calcimimetic compound, is effective in reducing parathyroid hormone (PTH) levels in approximately 70% of patients with secondary hyperparathyroidism. However, interindividual variations in the dose required to achieve the treatment goal have been noted in clinical studies. Our investigation examined the genetic polymorphisms of the calcium-sensing receptor (CaSR) gene as one possible cause of the different responses to cinacalcet. We report data on seven end-stage renal failure patients who were treated with regular haemodialysis and who participated in clinical trials of cinacalcet. All patients had secondary hyperparathyroidism with baseline intact PTH (iPTH) levels greater than 600 pg/ml. Three patients were male and four female with a mean+/-SD age of 60+/-12 years. DNA was extracted from peripheral lymphocytes. An area in exon 7 of the CaSR gene was amplified by the polymerase chain reaction and sequenced. Mean+/-SD baseline iPTH was 1086+/-189 pg/ml. The five patients without Arg990Gly demonstrated a 29.7+/-4.0% (+/-SEM) reduction in iPTH from individual baseline. One patient was found to be homozygous for the Arg990Gly polymorphism and another was heterozygous for both arginine and glycine alleles. The homozygous patient showed a significantly higher sensitivity to cinacalcet compared to the other patients (P=0.003) with a 76.3+/-7.7% reduction in iPTH from baseline. No polymorphisms were noted in codons 986 or 1011. This preliminary study points to the possibility that patients homozygous for glycine at the 990 position in exon 7 of the CaSR may be more sensitive to the calcimimetic drug cinacalcet compared to those who are homozygous for arginine at that location.

BACKGROUND

Lanthanum carbonate (LC) is a non-calcium-containing phosphate binder and shows a comparable effect with other phosphate binders on hyperphosphatemia in dialysis patients. LC also contributes to a reduced oral calcium load compared with calcium carbonate (CaC) treatment. However, no crossover studies which compare the influence on serum calcium level between treatments with LC and CaC in hemodialysis (HD) patients have been carried out.

METHODS

After washout for 2 weeks, 50 patients on HD were randomized (1 : 1) to receive LC or CaC for 3 months. Thereafter, patients underwent a second 2-week washout period and were switched to the alternative binder for the next 3 months. Mineral and bone metabolism markers were measured with the changes of vitamin D doses.

RESULTS

The serum phosphate level showed a similar decrease from baseline to 3 months in both groups. During the study periods, hypercalcemia was observed only in patients taking CaC. The dose of vitamin D analogue was increased more frequently in the patients of the LC group compared with LC group. The iPTH level showed a significant decrease in the CaC group, but not in the LC group. Serum levels of BAP, TRAP5b, and ALP were significantly elevated in the LC group, whereas the FGF-23 level showed a significant decrease.

CONCLUSIONS

LC effectively reduced the serum phosphate level (like CaC) and allowed the vitamin D analogue dosage to be increased without hypercalcemia in HD patients. LC is one of the useful phosphate binders without hypercalcemia. (UMIN-CTR registration number: UMIN000002331).

Hyperparathyroidism may play a role in the excess morbidity and mortality in chronic kidney disease. This study examined utilization and outcomes of patients with hyperparathyroidism and chronic kidney disease. In a US health maintenance organization (HMO), patients with chronic kidney disease were identified from the electronic medical record. Patients included in the study had at least one intact parathyroid hormone (iPTH) measurement ordered by a nephrologist and were at least 20 years of age with no history of renal replacement therapy (RRT, n = 455). Cohorts were determined by index iPTH level and were followed for 1 year. Rates of health care utilization were compared between cohorts using Poisson regression; costs comparisons were made using linear regression; mortality and RRT were evaluated using Cox regression. Increasing levels of iPTH were associated with a significantly elevated risk of mortality and RRT, even after adjustment for potential confounders such as stage of chronic kidney disease. Compared to iPTH of <110 pg/ml, we found a 66% increase combined mortality-RRT risk (HR 1.66, 95% CI 1.41-1.97) for those with iPTH 110-199 pg/ml, and a HR of 4.57 (95% CI 3.86-5.43) for iPTH>>or=300 pg/ml. We did not find a convincing association between iPTH level and utilization. While this study provides no evidence that treating patients with higher levels of iPTH will ameliorate poor outcomes, it suggests that iPTH levels beyond the targets suggested by clinical guidelines are associated with increased harm in patients with chronic kidney disease.

Aluminum (Al) may cause both osteomalacia and encephalopathy in dialysis patients. Little is known about the biology of Al. This study examined the initial distribution kinetics of Al and its biological effects after injections of 1 mg/kg/day into dogs for 3 to 5 weeks. Following one intravenous dose, the plasma half-life (x +/- SE) was 276 +/- 51.8 min, with an apparent volume of distribution of 1.30 +/- 0.17 liters or 5.90 +/- 0.30% body wt; 10 to 21% of administered Al was excreted in the urine over 150 min, and the renal contribution to plasma clearance of Al correlated with GFR (r = 0.77, P less than 0.05). The total plasma clearance of Al (4.43 +/- 2.83 ml/min) exceeded the renal contribution to plasma clearance (1.94 +/- 0.36 ml/min) in each dog, and in only two instances did the renal contribution reach 50% of total plasma clearance. Serum calcium rose from 9.4 +/- 0.2 to 11.1 +/- 0.3 mg/dl and immunoreactive parathyroid hormone (iPTH) fell by 27 +/- 4% following one Al injection. With repeated Al injections, serum calcium increased from baseline levels of 10.2 +/- 0.07 mg/dl to 11.1 +/- 0.22 and 11.3 +/- 0.46 mg/dl after 1 and 2 weeks, respectively. Renal function declined in all dogs, and serum creatinine exceeded 3.5 mg/dl in four; over the 5 weeks of study, serum calcium correlated with serum creatinine (r = 0.91, P less than 0.001). Liver, kidney, and spleen showed the highest tissue content of Al, and there was substantial uptake by bone; the parathyroid content of Al was modest.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the effect of androgens on body composition and muscle strength, we measured fat-free mass (kg), fat mass (kg), and bone density (g/cm2) by dual x-ray absorptiometry, and muscle strength (Newton meters) by dynamometry in a controlled, prospective study involving 13 nonathletic men receiving testosterone enanthate 200 mg/week in for 6 months and 8 healthy controls. Biochemical markers of bone turnover were measured in the treated subjects at baseline and 6 months. In the treated subjects at 6 months, fat-free mass (mean +/- SEM) increased by 9.6 +/- 1.0% (P < or = 0.01) whereas fat mass decreased by 16.2 +/- 6.7% (P < or = 0.05). Changes in muscle strength ranged from -1.6-19.2%. Only hip adduction increased 19.2 +/- 9.5% (P < 0.05). Changes in bone density ranged from -1.3-5.2%, decreasing significantly at one site and increasing significantly at four of the nine sites measured (P < 0.05). Serum testosterone increased by 91.1 +/- 7.5% (P < 0.01), and testicular volume decreased by 24.0 +/- 3.2% (P < 0.01). Serum osteocalcin increased by 35.7 +/- 17.3% (P < 0.05), serum immunoreactive PTH (iPTH) increased by 41.4 +/- 15.1% (P < 0.05), serum calcium decreased by 2.3 +/- 1.0% (P < 0.05), and serum albumin decreased by 4.5 +/- 1.7% (P < 0.05). There were no detectable changes in fat-free mass, fat mass, muscle strength, or bone density in controls. The administration of testosterone enanthate in pharmacological doses for 6 months resulted in a modest reduction in fat mass and small increases in fat-free mass, muscle strength, and bone density. These changes do not support the use of androgens for enhancing athletic performance.

Lactation-associated bone loss has been reported in adolescent mothers. Polymorphisms in the vitamin D receptor (VDR) gene may contribute to differences in the physiologic skeletal response to lactation in these mothers. We evaluated the influence of VDR gene polymorphisms ApaI, BsmI, and TaqI on bone mass, bone and calcium-related hormones, and breast milk calcium of lactating adolescents with habitually low calcium intake. Total body bone mineral content (TBMC), total body bone mineral density (TBMD), lumbar spine BMD (LSBMD), serum hormones [intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, insulin-like growth factor-I (IGF1), prolactin, and estradiol), and breast milk calcium were measured in 40 lactating Brazilian adolescents (15-18 y), and compared by VDR genotype subgroups after adjustment for calcium intake and postmenarcheal and lactational periods. TBMD and LSBMD Z scores were -0.55 +/- 1.01 and -1.15 +/- 1.48, respectively. LSBMD was higher (21%; P < 0.05) in adolescents with the aa genotype (n = 5) compared with those with the AA genotype (n = 7). TBMC and IGF1 were higher (23 and 50%, respectively; P < 0.05) in adolescents with tt (n = 4) than those with TT (n = 29) and Tt (n = 7) genotypes. Breast milk calcium and serum iPTH were higher (24 and 80%, respectively; P < 0.05) in adolescents with bb (n = 8) compared with those with BB (n = 21) genotype. These results indicate that bone mass and breast milk calcium are significantly associated with VDR genotypes in lactating Brazilian adolescents. Those with aa and tt genotypes had a better bone status and those with bb genotype had greater breast milk calcium.

The purpose of this study was to determine how serum 1,25(OH)2D, renal production of [3H]1,25(OH)2D and [3H]24,25(OH)2D from [3H]25(OH)D, and serum IPTH change with age and dietary Ca restriction. Male Fischer 344 rats aged 3, 13, and 25 mo were placed on either a high-Ca (1.2%) or low-Ca (0.02%) vitamin D-replete diet. After 4 wk, serum was collected, and renal conversion of [3H]25(OH)D3 to [3H]1,25(OH)2D3 and [3H]24,25(OH)2D3 was measured in vitro using isolated renal cortical slices. Serum 1,25(OH)2D and renal [3H]1,25(OH)2D3 production were markedly reduced in 13- and 25-mo-old rats compared with 3-mo-old rats fed the low-Ca diet. In 3-mo-old rats, feeding the low-Ca diet increased serum 1,25(OH)2D by 18-fold and renal [3H]1,25(OH)2D3 production by threefold compared with feeding the high-Ca diet. In 25-mo-old rats, dietary Ca had no effect on these parameters. Renal [3H]24,25(OH)2D3 production was increased in the 13- and 25-mo-old rats compared with the 3-mo-old rats. Serum IPTH increased with age regardless of diet and was significantly increased by the low-Ca diet in 3-mo but not in 13- or 25-mo-old rats. The changes in serum 1,25(OH)2D and renal [3H]1,25(OH)2D3 production observed in this study may account for the previously observed age-related decline in intestinal Ca absorption in this animal model.

Optimal vitamin D concentrations for bone health have not been determined in the Korean population. The aim of this study was to define serum 25-hydroxyvitamin D (25[OH]D) concentrations that indicate insufficiency among older Korean adults as measured by serum intact parathyroid hormone (iPTH) concentrations and bone mineral density (BMD). We analyzed data from the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV-3), which was conducted in Korea in 2009. We enrolled 1,451 men and 1,870 women aged 49 years and above. After adjusting for variables that could potentially affect serum 25(OH)D concentrations, we found that serum iPTH concentrations began to increase at serum 25(OH)D concentrations below 12.1 ng/mL (30.2 nmol/L). In addition, total-femur BMD increased until serum 25(OH)D concentrations dropped below 20.4 ng/mL (50.9 nmol/L); no significant changes were observed thereafter. Assuming that serum 25(OH)D concentrations below 12.1 and 20.4 ng/mL represent vitamin D insufficiency, the prevalences of vitamin D insufficiency were 8.7 and 50.4 % in men and 17.9 and 66.3 % in women, respectively. Serum 25(OH)D cutoff values of 12.1 ng/mL (OR = 1.26) and 20.4 ng/mL (OR = 1.54) were associated with osteoporosis (P < 0.01); osteoporosis was not associated with a 25(OH)D cutoff value of 30 ng/mL (75.0 nmol/L). In conclusion, serum 25(OH)D concentrations of 20 ng/mL might be sufficient for bone health in older Korean adults.

OBJECTIVE

To investigate influences of physical mobility and season on 25-hydroxyvitamin D-intact parathyroid hormone (iPTH) interaction in the elderly.

METHODS

We examined 188 frail institutionalized elderly at the expected nadir of their serum vitamin D concentrations (winter). This group was compared with 309 healthy ambulatory elderly at the expected time of maximum vitamin D repletion (summer), to accentuate the influences of season and physical activity.

METHODS

Serum concentrations of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, iPTH and urinary deoxypyridinoline (DPD) were measured.

RESULTS

Vitamin D metabolites were significantly lower in the institutionalized elderly (P<0.0001), with an 82.5% prevalence of vitamin D deficiency (25-hydroxyvitamin D <12ng/ml) in institutionalized elderly in wintertime and 15.5% in ambulatory elderly in summertime. Overall, median iPTH did not differ between groups. However, median iPTH secretion in the presence of low vitamin D serum concentrations (5-30ng/ml) was greater in ambulatory elderly. This could be explained by lower mobility status being correlated with greater serum calcium concentrations (r=0.24, P=0.02 in women; r=0.35, P=0. 001 in men) and greater urinary excretion of DPD (r=0.41, P=0.0001 in women; r=0.42, P=0.0002 in men), independent of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and iPTH.

CONCLUSIONS

These data support the hypothesis that immobility, even in the presence of vitamin D deficiency, acts as an overriding influence on bone metabolism by promoting bone resorption (measured as urinary DPD) and increasing serum calcium independent of iPTH. Therefore mobility status may substantially affect 25-hydroxyvitamin D threshold values and the degree to which patients benefit from vitamin supplementation.

BACKGROUND

Sevelamer hydrochloride, a major phosphate binder for patients on maintenance hemodialysis (MHD) is associated with reduced serum bicarbonate concentration due to hydrochloric acid release in the gut and to the binding of short chain fatty acids in the large intestine. Since metabolic acidosis can be deleterious, a study was devised to compare the time course of serum bicarbonate concentration during treatment with sevelamer hydrochloride or calcium carbonate.

METHODS

Sixteen well nourished patients on MHD who were in excellent clinical conditions and achieving target levels for blood pressure (BP) and hemoglobin (Hb), while on a protein intake of 1.1g/kg body weight (bw), were enrolled in the study. After a 2-week washout period, the patients were divided into two groups, each consisting of eight patients, and randomized either to 24 weeks of sevelamer followed by 24 weeks of calcium carbonate (group A) or to 24 weeks of calcium carbonate followed by 24 weeks of sevelamer (group B). Protein intake, n-protein catabolic rate (nPCR), serum concentrations of calcium, phosphate, calcium x phosphate (Ca x P) product, bicarbonate, intact parathyroid hormone (iPTH) and albumin were monitored. Time course changes in serum bicarbonate concentrations in relation to short and long dialytic intervals (48 vs. 72 hr) were also investigated.

RESULTS

Both sevelamer and calcium carbonate effectively controlled serum phosphate and the Ca x P product. During calcium carbonate treatment plasma phosphate concentrations were significantly below those of patients on sevelamer. Plasma bicarbonate concentration fell within target DOQI values during calcium carbonate administration both in group A and in group B, a goal which was not achieved under sevelamer administration. After a long dialytic interval in patients on sevelamer, serum bicarbonate concentration averaged 17.3 +/- 1.1 mEq/L, whereas it averaged 21.1 +/- 0.7 mEq/L in patients on calcium carbonate (p<0.01). Finally, a 24-week sevelamer administration caused a statistically significant (p<0.05) reduction (0.8 g/dL) in serum albumin concentration, without affecting iPTH. Taken together, these results indicate that sevelamer worsens metabolic acidosis, which needs to be corrected.

OBJECTIVE

To explore associations between vitamin D and cardiovascular disease risk factors in young European adults.

METHODS

This was a cross-sectional analysis of serum 25-hydroxyvitamin D [s25(OH)D], intact parathyroid hormone (iPTH) and biomarkers of cardiovascular disease risk in 195 healthy 20- to 40-year-olds (109 women) with a BMI between 27.5 and 32.5 from Iceland (64° N; n = 82), Ireland (51° N; n = 37) and Spain (42° N; n = 76) during mid-late winter.

RESULTS

The median s25(OH)D was 52.8 nmol/l (IQR 38.1-69.9) or 21.1 ng/ml (IQR 15.2-28.0) with a latitude-dependent gradient (p ≤ 0.0001): Iceland, 41.7 nmol/l (IQR 32.7-54.2) or 16.7 ng/ml (IQR 13.1-21.7); Ireland, 52.9 nmol/l (IQR 35.3-68.6) or 21.2 ng/ml (IQR 14.1-27.4), and Spain, 67.1 nmol/l (IQR 47.1-87.1) or 26.8 ng/ml (IQR 18.8-34.8). Eleven percent of Icelandic participants had s25(OH)D concentrations <25 nmol/l (10 ng/ml) and 66% of Icelandic, 43% of Irish, and 30% of Spanish volunteers had concentrations <50 nmol/l (20 ng/ml), respectively. Overall, 17% met 3 or more of the NCEP/ATP III criteria for cardio-metabolic syndrome (MetS). Participants in the lowest third of s25(OH)D [≤ 42.5 nmol/l (17 ng/ml)] were more likely to have MetS (OR 2.49, p = 0.045) and elevated TAG (OR 3.46, p = 0.019). Individuals with iPTH concentrations in the lowest third [2.34 pmol/l (22.2 pg/ml)] were more likely to have elevated fasting TAG (OR 4.17, p = 0.039), insulin (OR 3.15, p = 0.029) and HOMA-IR (OR 2.15, p = 0.031), and they were less likely to have elevated IL-6 (OR 0.24, p = 0.003).

CONCLUSIONS

There were interactions between s25(OH)D, iPTH and cardio-metabolic risk factors which, given the increasing prevalence of overweight and obesity and a low vitamin D status among adults, require randomised controlled vitamin D intervention studies in overweight persons.

Bone disease with total parenteral nutrition (TPN) has been attributed to aluminum loading or vitamin D therapy. We studied 17 patients who first received TPN containing casein hydrolysate with high Al and ergocalciferol (25 micrograms/d) for 6-72 mo followed by TPN containing amino acids with reduced Al and ergocalciferol (5 micrograms/d) for 9-58 mo. We also did a cross-sectional study of 22 patients receiving casein and ergocalciferol (25 micrograms/d) compared with 46 patients receiving amino acids and ergocalciferol (5 micrograms/d) for 6-58 mo. Bone formation was higher and osteoid area, bone-surface stainable Al and total bone Al were lower with amino acid TPN than with casein TPN. Bone formation varied inversely with both plasma Al and bone-surface Al, suggesting that plasma or bone-surface Al, acquired during TPN, can reduce bone formation and lead to patchy osteomalacia. Serum levels of iPTH and 1,25-dihydroxyvitamin D were higher with amino acid TPN.