In athymic mice we have developed a model of long-term human PTH hypersecretion, using xenotransplantation of respectively parathyroid gland fragments obtained from patients with primary (primary) or secondary (secondary) uremic hyperparathyroidism (HPT), and parathyroid cells maintained in culture from patients with secondary uremic HPT. Both grafted parathyroid tissue fragments and cultured cells induced prolonged and marked secretion of human intact PTH (iPTH) in nude mice. Despite extremely high plasma iPTH levels, hypercalcemia or hypophosphatemia was not observed. Moreover, PTH secretion was not significantly modified by low-calcium, high-phosphate diet for 3 weeks. Four mice which had a mean plasma human iPTH level of 237+/-152 pg/ml for more than 9 months and 4 age-matched, sham-grafted control mice with undetectable human iPTH levels underwent bone histomorphometry examination. No difference was found between the two groups with respect to active bone resorption surface or number of osteoclasts/mm2. We hypothesize that the characteristic deficit of T cell function and of cytokine and growth factor production may protect nude mice with chronic hypersecretion of human PTH from hypercalcemia and bone lesions. We suggest that this strain of mice could be used for better understanding the relationship between cytokines and bone turnover.

BACKGROUND

Kidney transplantation (KTx) restores many of the disorders accompanying end-stage renal failure. However, hypercalcemia and hypophosphatemia are both common complications after renal transplantation. Prospective observation of these complications has not been well described and pre-transplant predictors also remain unknown. This prospective observational cohort study was carried out to clarify pre-transplant risk factors of persistent hypophosphatemia and/or hypercalcemia at 12 months after transplantation.

METHODS

Consecutive living donor KTx recipients (n = 39) at Tokyo Women's Medical University were prospectively recruited. Parameters of bone and mineral metabolism including intact parathyroid hormone (iPTH) and full-length fibroblast growth factor (FGF) 23 were followed.

RESULTS

FGF23 decreased to comparable levels for renal function while hyperparathyroidism persisted at 12 months after transplantation. Multivariate linear regression analysis revealed that pre-transplant iPTH correlated with hypercalcemia at 12 months and pre-transplant FGF23 was the best pre-transplant predictor of persistent hypophosphatemia at 12 months.

CONCLUSIONS

It is intriguing that although FGF23 is not a causal factor for hypophosphatemia at 12 months post-transplantation, it is a significant predictor of this common complication.

The objectives were to determine the prevalence of vitamin D deficiency [25(OH)D < 10 ng/ml] in pediatric renal transplant (RTx) recipients, compared with controls and identify correlates of changes in 25(OH)D and intact parathyroid hormone (iPTH) levels following transplantation. Serum 25(OH)D, 1,25(OH)(2)D, and iPTH were measured once in 275 healthy controls and at transplantation, and 3 and 12 months posttransplantation in 58 RTx recipients. Multivariate logistic regression models determined the odds ratio (OR) of vitamin D deficiency in RTx recipients vs. controls adjusted for age, sex, race, and season. Generalized estimating equations were used to assess changes following transplantation. At transplantation, 22% of nonblack and 27% of black RTx recipients were vitamin D deficient. The adjusted OR of vitamin D deficiency was greater in RTx recipients (p < 0.001) compared with controls; however, the transplant association was greater in nonblack vs. black individuals (interaction p = 0.02). Overall, 25(OH)D levels did not change significantly following transplantation. Younger age (p < 0.01), nonblack race (p < 0.001), visits in nonwinter months (p < 0.001), and supplementation with ≥400 IU/day ergo/cholecalciferol (p < 0.001) were associated with increases (or lesser declines) in 25(OH)D following transplantation. Increases in 25(OH)D levels (p < 0.001) and vitamin D supplementation (p < 0.01) were associated with greater reductions in iPTH levels following transplantation, independent of 1,25(OH)(2)D levels.

In the surgical treatment of secondary hyperparathyroidism (2HPT) of chronic kidney disease (CKD), a parathyroidectomy (PTx) of 4 glands can only be presumed as 'total', and indications for autoimplantation are complex. Intraoperative rapid parathyroid hormone assay could be useful to predict a radical resection. We evaluated iPTH levels 20 min and 24 h after a 4-gland PTx in 35 patients to determine the predictive value of intraoperative iPTH assay. We analysed retrospectively 35 patients affected by 2HPT of CKD, 13 undergoing total parathyroidectomy (TP) and 22 TP + autoimplantation (TPai), after removing 4 glands in 33 cases and 5 glands in 2. Intact PTH assays were acquired after 40 min before induction of anaesthesia, after removing both ipselateral glands, at 20 min after surgery and on postoperative day 1. 20 min after 4-gland PTx, a decrease of iPTH levels >80 % of the preoperative value was observed in 27 of 35 cases (77.1 %) and <80 % in 8 of 35 cases (22.8 %). In 6 of these 8 patients, iPTH levels were within the normal range 24 h after surgery. Although the intraoperative iPTH assays are of interest in the treatment of 2HPT, the predictive value of this method is not entirely satisfactory. In fact, a 4-gland PTx ensures euparathyroidism in most cases, even when intraoperative iPTH assays are not trustworthy; however, intraoperative iPTH assay, although not a perfect 'tool', is a proved aid for the surgeon in making his decision.

OBJECTIVE

This study examined differences in the concentration of markers of mineral metabolism across race in patients with advanced CKD not requiring dialysis and ESRD.

METHODS

Concentrations of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)(2)D), intact parathyroid hormone (iPTH), and fibroblast growth factor 23 (FGF-23) were measured in stored plasma samples of 1497 patients with advanced CKD not yet on dialysis and ESRD who participated in the Homocysteine in Kidney and End Stage Renal Disease study. Linear regression models were used to examine the relationship between race and 25(OH)D, 1,25(OH)(2)D, iPTH, and FGF-23 concentrations.

RESULTS

Non-Hispanic white patients comprised 58% of the cohort, whereas non-Hispanic blacks comprised 42%. Median (interquartile range) FGF-23 concentrations were lower in blacks compared with whites with CKD (323 [181-655] versus 431 [232-1026] RU/ml; P<0.001) but not in ESRD. In adjusted linear regression models, blacks with CKD not requiring dialysis had significantly lower plasma FGF-23 concentrations (difference, -159; 95% confidence interval, -205 to -106; P<0.001) compared with whites, independent of plasma 25(OH)D, 1,25(OH)(2)D, and iPTH concentrations. This difference was not observed in the ESRD group. The magnitude of correlation for the relationships between 1,25(OH)(2)D with iPTH, FGF-23 with 1,25(OH)(2)D, and FGF-23 with iPTH were stronger among blacks than whites with CKD not requiring dialysis.

CONCLUSIONS

In advanced CKD not requiring dialysis, blacks have lower FGF-23 concentrations than whites. Blacks with CKD and ESRD have lower 25(OH)D and higher iPTH compared with whites, independent of FGF-23 concentrations.

Plasma PTH concentrations were determined in rats with an antiserum to human PTH (1-34) that cross reacts with rat PTH in order to evaluate the effects of growth, vitamin D deficiency and dietary modulations of plasma calcium. Displacement curves for synthetic rat PTH (1-34) and diluted rat plasma were parallel with curves for the hPTH (1-34) standards and hPTH (1-84). Parathyroidectomy in 33-day-old rats resulted in a fall in iPTH from (mean +/- SE) 8.1 +/- 0.5 to 5.4 +/- 0.5 pg/ml in an assay in which the lowest detectable concentration was 3 pg/ml. Elevation of plasma Ca by 0.7 mg/dl by dietary calcium supplementation in 25-day-old pups led to a plasma iPTH level of 4.4 +/- 0.7 pg/ml compared with 9.9 +/- 0.7 pg/ml in controls. There were no significant changes in iPTH in control rats fed a complete diet containing 0.4% Ca and 0.4% P over the age range 14-56 days. Rat pups (-D) suckling vitamin D-deprived mothers had plasma Ca and iPTH values of 7.76 +/- 0.16 mg/dl and 173 +/- 27 pg/ml, respectively, at 25 days of age and 5.8 +/- 0.2 mg/dl and 677 +/- 85 pg/ml, respectively, at 56 days. The -D pups that had access to their mothers' calcium-supplemented diet (1.6% Ca and 1.4% P) had a mean plasma Ca value that was 0.5 mg/dl above that of the control group and a mean plasma iPTH level of 6.7 +/- 0.8 pg/ml. We suggest that the RIA for PTH measures mostly, if not entirely, bioactive PTH. We conclude that plasma iPTH (a) remains essentially unchanged in normal rats during the rapid growth period, (b) can increase up to 75-fold in hypocalcemic vitamin D-deficient rats, and (c) can be suppressed to barely detectable levels when plasma Ca is raised less than 1 mg/dl above the level of normal control rats.

OBJECTIVE

Patients with primary hyperparathyroidism (PHPT) and/or hypercalcemia are at increased risk for myocardial ischemia. Whether PHPT is associated with altered endothelium-dependent dilation, vascular smooth muscle cell function, or both is unknown. This study was performed to test the hypothesis that endothelium-dependent, flow-mediated dilation (FMD) and/or endothelium-independent, nitroglycerin-induced dilation (NMD) is impaired in the preclinical phase of vascular disease in patients with PHPT.

METHODS

Twenty-six PHPT patients (mean +/- SD; age 55 +/- 15 y, serum calcium 3.00 +/- 0.37 mmol/l, serum phosphate 0.79 +/- 0.21 mmol/l, iPTH 249 +/- 262 pg/ml) with no evidence of coronary artery disease (CAD) as well as 26 normocalcemic control subjects (CTL; age 51 +/- 12 y) were studied. FMD following reactive hyperemia and NMD after 0.8 mg nitroglycerin (NTG) were assessed in the brachial artery by using high resolution ultrasound (7 MHz).

RESULTS

NMD was impaired in PHPT patients compared to CTL (11.9 +/- 3.9% vs. 15.6 +/- 5.7%; p = 0.012). FMD was similar in both study groups (11.6 +/- 4.6% vs. 12.6 +/- 4.9; NS). The ratio of FMD to NMD was significantly different between PHPT patients and CTL (0.98 +/- 0.19 vs 0.81 +/- 0.25, p = 0.0009). On multiple stepwise regression analysis serum calcium was independently associated with the FMD/NMD ratio (r = 0.34, p = 0.017).

CONCLUSIONS

Endothelium-independent vasodilation is impaired in PHPT patients without clinical evidence of coronary artery disease compared to normocalcemic CTL, while endothelium-dependent dilation was similar in both study groups. Thus, altered arterial reactivity in the course of PHPT may predominantly involve the arterial media and not the endothelium as observed previously in patients with various stages of atherosclerosis.

Twenty chronically azotemic patients (experimental group) with a mean creatinine clearance of 22.5 +/- 9.4 ml/min followed a diet supplying daily, per kilogram of body weight, 7.0 mg of phosphorus and 0.5 g of protein, mostly of high biological value, for 11.3 months. A group of 19 similar patients (control group) followed a diet supplying daily, per kilogram of body weight, 12 mg of phosphorus and 0.8 g of protein for a similar period of time. In the experimental group, the serum inorganic phosphorus, urea, and iPTH (both N-terminal and C-terminal fragments) decreased significantly. The creatinine clearance decreased by -0.59 +/- 0.7 ml/min per month prior to the commencement of the experimental diet and increased by a mean of 0.1 +/- 0.4 ml/min per month during the period of study. In the control group, the serum inorganic phosphorus increased, the serum urea and iPTH remained practically constant, and the mean creatinine clearance continued to decrease at a rate not significantly different from that prior to the onset of the study (-0.50 +/- 0.66 and -0.44 +/- 0.10 ml/min per month, respectively). The mechanisms by which the low-phosphorus, low-nitrogen diet slows the progression of renal failure are discussed, and the practical importance of prescribing the dietetic restriction early in the course of renal disease is stressed.

Nine patients with vitamin D-dependency type I were studied. We observed that treatment with large doses of vitamin D altered the phenotypic expression of the disease, thus making a delayed diagnosis difficult. At the time of entry, eight children had hypocalcemia, and seven had hypophosphatemia. Elevated serum immunoreactive parathyroid hormone and low (less than 3 SD from control mean) 1 alpha,25-dihydroxyvitamin D values were constant findings, with no vitamin D deficiency. Despite the elevated serum iPTH, three children had normal urinary phosphate excretion and five had normal urinary cAMP excretion. In the five children tested before treatment, there was no significant change in renal phosphate excretion during an acute parathyroid hormone infusion, although in all a significant rise of urinary cAMP occured. Treatment with calcitriol (0.25 to 2 microgram/day) returned all the biochemical values to normal within four months. In two patients, both supplemented with vitamin D, histomorphometric analysis of iliac crest biopsies revealed severe osteomalacia. After nine and ten months of treatment with calcitriol, there was histologic evidence for improvement of bone mineralization. Since calcitriol requirements may vary during the course of treatment, careful monitoring of biochemical variables is essential.

BACKGROUND

The need for intraoperative parathyroid hormone (iPTH) assays in minimally invasive parathyroidectomy (MIP) remains controversial. We report the results of MIP performed without the use of iPTH assays.

METHODS

This was a single-institution retrospective review of patients with primary hyperparathyroidism treated with MIP between October 1, 1998, and December 31, 2002.

RESULTS

Seventy-seven patients were studied. The mean preoperative calcium level was 11.4 mg/dL. All patients had a normal calcium level postoperatively (range, 7.4-10.2 mg/dL, mean, 9.1 mg/dL). Three patients (4%) required re-exploration for various reasons including the development of a second adenoma, secondary hyperparathyroidism, and discordant pathology. All 3 patients initially were eucalcemic.

CONCLUSIONS

Our success rate of 96% using a combination of preoperative sestamibi scans, intraoperative gamma probe localization, and selective frozen pathology is consistent with the published success rates using iPTH assays of 95% to 100%. We conclude that MIP can be performed successfully without using iPTH assays.

The effects of suppressive doses of levothyroxine (LT4) on bone mass are controversial. Our aim was to evaluate the effects on axial and appendicular bone mineral density (BMD) and bone metabolism of long-term LT4 suppressive therapy in women by means of cross-sectional and longitudinal studies, and also to assess the potential influence of menopausal status and LT4 dose. Seventy-six women (aged 47 +/- 13 years, 37 pre- and 39 postmenopausal) on suppressive therapy (67 +/- 34 months duration, mean LT4 dose 168 +/- 41 micrograms/day) from our Thyroid Cancer Unit without previous hyperthyroidism or concomitant hypoparathyroidism were studied. Serum TSH, T3 free T4, calcium, phosphorus, alkaline phosphatase, BGP, iPTH and urinary calcium (uCA) were measured. BMD was measured by dual-energy X-ray absorptiometry (DXA) at lumbar spine, femoral neck, Ward's triangle, ultradistal and distal third radius and expressed as a Z-score. In a subset of 27 women aged 46 +/- 15 years (14 pre- and 13 postmenopausal) a second densitometry scan was performed 27 +/- 5 months later. Patients on suppressive therapy showed a small reduction in BMD at the distal third radius (Z-score: -0.77 +/- 0.98; 95% confidence interval: -1.11, -0.44) without differences between pre- and postmenopausal women. Significant relations with the regimen of suppressive therapy and bone turnover markers were detected except at the lumbar spine. In the longitudinal study a significant although mild reduction in femoral neck BMD was found that correlated with prior T3 and iPTH. In conclusion, our data show a small detrimental effect of cautious LT4 suppressive therapy on bone mass assessed by DXA; it remains to be established whether this increases the prevalence of fractures.

OBJECTIVE

Current clinical assays for total 25-hydroxy (OH) vitamin D measure vitamin D bound to vitamin D-binding protein (DBP) and albumin plus unbound ('free') D. We investigated the relationship between total and free 25(OH)D with bone metabolism markers in normal (>3.5 g/dl) vs. low (≤3.5 g/dl) albumin cirrhotics.

METHODS

Eighty-two cirrhotics underwent measurement of free and total 25(OH)D by immunoassay, DBP and markers of bone metabolism [intact parathyroid hormone (iPTH), C-telopeptide (CTX), bone-specific alkaline phosphatase (BSAP), osteocalcin, amino-terminal pro-peptide of type 1-collagen (P1NP)]. Pearson's coefficients assessed relevant associations.

RESULTS

Cirrhotics with low (n = 54) vs. normal (n = 28) albumin had lower total 25(OH)D (12.1 vs. 21.7 ng/ml), free 25(OH)D (6.2vs.8.6 pg/ml) and DBP(91.4 vs. 140.3 μg/ml) [P < 0.01 for each]. iPTH was similar in low and normal albumin groups (33 vs. 28 pg/ml; P = 0.38), although serum CTX(0.46vs.0.28 ng/ml) and BSAP(31.7 vs. 24.8 μg/L) were increased (P < 0.01). An inverse relationship was observed between total 25(OH)D and iPTH in normal (r = -0.47, P = 0.01) but not low albumin cirrhotics (r = 0.07, P = 0.62). Similar associations were seen between free 25(OH)D and iPTH(Normal: r = -0.46, P = 0.01; Low: r = -0.03, P = 0.84). BSAP, osteocalcin and P1NP were elevated above the normal range in all cirrhotics but not consistently associated with total or free 25(OH)D.

CONCLUSIONS

Cirrhotics with low vs. normal albumin have lower levels of DBP, total and free 25(OH)D. The expected relationship between total or free 25(OH)D with iPTH was observed in normal but not in low albumin cirrhotics, demonstrating that total 25(OH)D is not an accurate marker of bioactive vitamin D status in cirrhotics with synthetic dysfunction. Additional investigation into the role of vitamin D supplementation and its impact on bone mineral homoeostasis in this population is needed.

Previous studies have shown that estrogen therapy in postmenopausal women results in an increase in serum immunoreactive parathyroid hormone (iPTH) levels. It has been assumed that this effect of estrogen on PTH secretion is indirect, being mediated via mild hypocalcemia resulting from an inhibition of bone resorption. We evaluated the direct effect of 17 beta-estradiol (E2) and of progesterone (Prog) on secretion of PTH from bovine parathyroid tissue in vitro. Both E2 and Prog caused a significant stimulation of PTH secretion within one hour, which was progressive for the three-hour observation period. The responses were dose-related from 10(-7) to 5 X 10(-10) mol/L. There was no PTH response to 10(-7) mol/L alpha-E2, 3-methoxy estriol, estrone, testosterone, or 20-alpha-hydroxy progesterone, indicating specificity of the responses to E2 and Prog. There was a minimal PTH secretory response to 10(-6) mol/L cortisol and 10(-6) mol/L estrone. The E2 receptor antagonist tamoxifen did not inhibit the E2 effect on PTH secretion. This observation plus the rapid PTH response suggests that this hormonal effect may not be via the conventional intracellular E2 receptor. Therefore, E2 and Prog can stimulate PTH secretion by rapid, direct, and specific effects on parathyroid cells. These gonadal hormones may, therefore, be important in calcium homeostasis via their direct stimulatory effect on PTH secretion.

Osteocalcin(OC) is a specific serum parameter of bone formation. Since bone metabolism disturbances, including osteoporosis, are seen in paraplegia, the serum levels of OC, midregional parathyroid hormone(mPTH), intact para-thyroid hormone (iPTH) and calcitonin (CT) serum levels were determined in 13 patients with paraplegia or tetraplegia and 15 control subjects by radioimmunoassay in a cross sectional study. In addition, the urinary hydroxyproline/creatine and the urinary calcium/creatinine ratio was determined. Serum OC levels were significantly increased in the patients with spinal cord injury (p less than 0.02), whereas serum levels of mPTH, iPTH and CT were not statistically different. The urinary hydroxyproline/creatinine ratio was significantly higher in the patients than in the controls (p less than 0.02), and the urinary calcium/creatinine ratio also tended to be higher in the patients. In a follow up study over 6 months after spinal cord injury, serum OC, serum iPTH, urinary hydroxyproline/creatinine ratio and the calcium/creatinine ratio were determined in 6 patients at monthly intervals. Hyperhydroxyprolinuria preceded the gradual increase of serum OC from normal to clearly elevated levels. Our data suggest that increased bone resorption in paraplegia is linked to an enhanced osteoblastic activity.

OBJECTIVE

Osteoporosis has been recognized in patients with liver cirrhosis, although the prevalence and the exact mechanisms vary considerably in the literature. We have studied the prevalence of bone disease in cirrhotic patients, the pathogenesis and the relation to the etiology and the severity of liver failure.

METHODS

The study included 83 hospitalized patients with various types of cirrhosis, where 25 healthy individuals served as controls. Patients were classified according to Child-Pugh's stages as follows: Child A: 49, Child B: 20, Child C: 14. Serum levels of iPTH, 250HD, LH, FSH, SHBG, testosterone, estradiol, IGF-I, osteocalcin and urine levels of cross-linked N-telopeptides of collagen type 1 (NTX) were measured in all patients. Bone mineral density (BMD) was measured by DEXA at the spine of both patients and controls.

RESULTS

The prevalence of osteoporosis was higher in patients (26/83) 31.3% than in controls (4/25) 16%. Osteopenia was positively related with the elevated levels of crosslinked N-telopeptides (p=0.048). There were no differences in BMD between the types of cirrhosis. BMD was found to be significantly lower in Child B and C male patients than in Child A (p=0.043). Patients' groups B, and C had lower testosterone levels with a trend to contribute to the low BMD (p=0.15). 250HD and IGF-1 were significantly lower in decompensated cirrhosis (p<0.002), but did not correlate with BMD.

CONCLUSIONS

Cirrhosis is a major cause of osteoporosis and the degree of osteopenia is related to the severity and not the etiology of the liver disease. The biochemical markers of bone remodeling suggest a high-turnover osteoporosis in cirrhosis.

The rate of progression of renal failure has been evaluated in two homogenous groups of chronic renal patients with early insufficiency. In both groups the diet supplied the same amount of calories (approximately 35 Kcal/kg/day) and the protein intake was equally restricted (approximately, 0.6 g/kg/day); however, in Group 1 the phosphorus intake was lower (6.5 mg/kg/day) than in Group 2 (12 mg/kg/day). In both groups the rate of decline of creatinine clearance decreased when patients changed from a free mixed diet to the specially controlled diets, but in Group 1 (lower phosphorus intake) this change was much more marked than in Group 2. Elevated mean levels of serum phosphate and of urinary output of phosphate per unit of creatinine clearance, and elevated mean levels of serum iPTH were found in the patients of Group 2, whereas Group 1 patients had normal mean levels of serum phosphate and of iPTH, and the phosphaturia per unit of creatinine clearance was almost normal. The role of such abnormalities in urinary and serum phosphate, and of secondary hyperparathyroidism, on the progression of renal failure is discussed.

The clinical value of measuring serum immunoreactive parathyroid hormone (iPTH) for the diagnosis of primary hyperparathyroidism is sometimes debated, and the clinical significance of an elevated postoperative serum iPTH level is unknown. Therefore we studied 141 consecutive patients with primary hyperparathyroidism before and after parathyroidectomy to determine the clinical value of measuring serum iPTH by a mid-region-specific radioimmunoassay. Eighty-eight percent of the patients with primary hyperparathyroidism had an absolute increase in the level of serum iPTH (greater than 40 microliter Eq/ml) before surgery, and the remaining patients had an inappropriately increased level of serum iPTH for the simultaneous serum calcium level. Preoperative serum iPTH level correlated positively with serum calcium level and parathyroid tumor size. Postoperative elevation of serum iPTH level was common (as high as 40%) and was associated with higher preoperative levels of blood urea nitrogen, serum creatinine, and alkaline phosphatase and larger tumors. An elevated postoperative serum iPTH level without hypercalcemia did not indicate a failed parathyroidectomy, whereas negative parathyroid exploration and postoperative hypercalcemia were the best predictors of persistent hyperparathyroidism. We conclude that preoperative serum iPTH measurement is a very sensitive diagnostic test for primary hyperparathyroidism, but postoperative serum iPTH measurement is not a good predictor for persistent or recurrent hyperparathyroidism.

We measured mineral and acid balances, serum iPTH, urinary cAMP/creatinine, and plasma concentrations of 25OHD and 1,25(OH)2D in 7 healthy adults during control conditions and during increased fixed acid production achieved either by the administration of NH4Cl (N = 3) or by increased dietary protein intake (N = 4). When acid production was increased, the subjects were in positive acid balance and negative Ca balance because of increased urinary Ca excretion. Serum iPTH fell slightly but urinary cAMP and the plasma levels of vitamin D metabolites did not change. W conclude that the accelerated skeletal and urinary losses of Ca that occur when fixed acid production is increased are not contributed to nor compensated for by the parathyroid-vitamin D endocrine systems.

It is a matter of debate whether vascular calcification and bone loss are simultaneously occurring but largely independent processes or whether poor bone health predisposes to vascular calcification, especially in patients with kidney disease. Here we investigated the association between the changes of microarchitecture in weight bearing bone and the extent of coronary artery calcification in patients with chronic renal failure. The bone microarchitecture of the tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT), bone mineral density using dual X-ray absorptiometry (DXA) of the lumbar spine, femoral neck and distal radius as well as coronary artery calcification using multi-slice CT and reported as Agatston score were measured in 66 patients with end-stage renal disease on chronic hemodialysis. Markers of bone turnover, vitamin D status and intact parathyroid hormone (iPTH) were assessed. CAC score was found to be <100 in 39% and ≥100 in 61% of patients. The median [95% CI] total CAC score was 282 [315-2587]. By univariate analysis, significant correlations between CAC and age (R=0.52, p<0.001), weight (R=0.3, p<0.01) and serum cross laps (CTX, R=-0.39, p<0.01) were found, and parameters of bone microarchitecture were numerically but not significantly lower in patients with CAC scores ≥100. In multivariate analysis stratifying for gender and correcting for age, tibial density (Dtot) and bone volume/total volume (BV/TV) were significantly lower in patients with CAC scores ≥100 (p<0.05 for both). Low trabecular bone volume and decreased cortical bone density are associated with coronary artery calcification in dialysis patients.

Selective percutaneous ethanol injection therapy (PEIT) of the parathyroid glands has been shown to be effective in chronic dialysis patients with severe secondary hyperparathyroidism. In this study, we examined whether it was possible to maintain parathyroid function within target range (intact parathyroid hormone [iPTH], 160 to 360 pg/mL) in the long term after successful destruction of hyperplastic tissue. PEIT was performed in 46 patients resistant to calcitriol pulse therapy, and all glands larger than 5 mm in diameter were destroyed by ethanol, guided by power Doppler flow mapping. Serum iPTH levels decreased from 633.3 +/- 359.9 to 226.3 +/- 204.7 pg/mL at 3 weeks and were maintained at 289.9 +/- 222.4 pg/mL at 1 year after PEIT. Total alkaline phosphatase activity decreased from 384.9 +/- 160.1 to 234.0 +/- 110.5 IU/L at 1 year after PEIT. In 19 patients, iPTH levels decreased into relative hypoparathyroidism (iPTH < 160 pg/mL) at 3 weeks after PEIT; however, they recovered at 1 year after PEIT (191.1 +/- 29.6 pg/mL). Parathyroid function was maintained within target range in 80.4% of the patients at 1 year after PEIT with appropriate medical therapy. Surgical parathyroidectomy was not required in any patient. Conversely, in eight other patients with recurrent hyperparathyroidism after subtotal parathyroidectomy, iPTH levels recovered in only 50% of the patients at 1 year after PEIT. Thus, destruction of hyperplastic tissue should be optimized in such patients. Recurrent nerve palsy was observed in only one patient, but was reversible. In conclusion, selective PEIT guided by color Doppler flow mapping is an effective and safe adjunct to medical therapy with a low risk for hypoparathyroidism.

BACKGROUND

Osteoporosis and chronic kidney disease are common conditions in older adults, and often occur concurrently. Bone disease is caused by increased bone turnover accompanying secondary hyperparathyroidism, and by factors such as bone metabolic disorder accompanying kidney disease and postmenopausal or age-related osteoporosis, even in hemodialysis patients. Raloxifene is commonly used for the treatment of postmenopausal osteoporosis in the general population, and may be a treatment option for osteoporosis in hemodialysis patients. However, the effects of raloxifene in hemodialysis patients with type 2 diabetes have not been examined in detail.

OBJECTIVE

This study was performed to investigate the effects of raloxifene on bone turnover markers and bone density in postmenopausal women with type 2 diabetes mellitus who were undergoing hemodialysis in Japan.

METHODS

The subjects were 60 female patients on maintenance hemodialysis (non-diabetic, n=30; diabetic, n=30). Raloxifene hydrochloride (60 mg) was administered to 14 diabetic patients and 14 non-diabetic patients for one year, and these patients were compared with control groups (no raloxifene) of 16 diabetic patients and 16 non-diabetic patients. Serum levels of N-terminal cross-linking telopeptide of type I collagen (NTx), bone alkaline phosphatase, and intact parathyroid hormone (iPTH) were measured, and bone density was determined by quantitative heel ultrasound at the speed of sound (SOS) in the calcaneus during this period.

RESULTS

There were no significant differences in the levels of bone turnover markers except for iPTH after treatment of diabetic and non-diabetic patients with raloxifene for one year. SOS increased after treatment with raloxifene, but was significantly decreased in the control groups. Treatment with raloxifene resulted in a significant decrease in NTx and a significant increase in SOS in both diabetic and non-diabetic patients. There were no significant differences between the diabetic and non-diabetic patients who received raloxifene.

CONCLUSIONS

Treatment with raloxifene can suppress reduction in bone density in postmenopausal women with type 2 diabetes who are undergoing hemodialysis.

BACKGROUND

The restless legs syndrome (RLS) is a movement disorder characterized by an imperative urge to move the legs, associated with paraesthesias, motor restlessness and worsening of symptoms at night with at least partial relief by activity. Its prevalence ranges between 2-15% of general adult population and 20-30% of uremic patients.

OBJECTIVE

To evaluate the frequency and the clinical features of RLS in a sample of general adult population and in uremic patients, in Chile, correlating it with biochemical parameters.

METHODS

100 relatives of outpatients and 166 uremic patients undergoing chronic haemodialysis were interviewed assessing the presence and severity of RLS according to current diagnostic criteria. Biochemical parameters assessed were hematocrit, serum ferritin, phosphate, intact parathyroid hormone (iPTH) levels.

RESULTS

13% of the general population sample was affected, 15% of them were severe. Forty three cases were found among uremic patients (25.9%) (p < 0.01 vs general population), 60% of them were severe and women were affected with higher frequency (p < 0.05) and severity (p < 0.01). Four patients presented RLS even during hemodialysis. No correlation was found with biochemical parameters. Most RLS cases had not been diagnosed previously.

CONCLUSIONS

In our population RLS is common and undetected. It is especially prevalent and severe in uremic patients: we found no evidence that anaemia, iron deficiency or iPTH level play a major pathogenic role. Our findings emphasize the need of greater medical awareness of RLS because available therapy may improve the quality of life.

BACKGROUND

Disturbed mineral metabolism is associated with increased morbidity and mortality, however, its influence on physical symptoms is less clear. We explored the effects of disordered plasma calcium, phosphorus, calcium-phosphorus (Ca x P) product and intact parathyroid hormone (iPTH) concentrations according to the K/DOQI guideline for bone metabolism and disease on the risk of muscle and skin complaints in dialysis patients.

METHODS

As part of NECOSAD, a prospective multicentre study in the Netherlands, we included 1469 consecutive patients who started haemodialysis or peritoneal dialysis between 1997 and 2004. Muscle pain, cramps and itching (pruritus) and dry (xerosis) skin were repeatedly measured using the Kidney Disease Quality of Life-Short Form questionnaire. Odds ratios (OR) for the risk of complaints over time were calculated by generalized estimating equations (GEE) models.

RESULTS

Mean age was 59 +/- 15 years, 61% of the patients were male and 63% were on haemodialysis. At baseline >65% of the patients had muscle and skin complaints. Compared with patients who met the target, the risk of muscle pain was increased in patients with hyperphosphataemia [OR: 1.2; 95% confidence interval (CI): 1.1-1.5] iPTH concentrations below the target range were associated with lower risk of cramps (OR 0.8, 95%CI: 0.6-0.9). The risk of pruritus was increased in patients with severely elevated plasma calcium (OR 1.4; 95%CI: 1.1-1.7), phosphorus (OR 1.4; 95%CI: 1.1-1.7) and Ca x P product levels (OR 1.6; 95%CI: 1.3-2.0). Finally, increased plasma calcium concentrations were associated with an elevated risk of xerosis (OR 1.4; 95%CI: 1.1-1.9).

CONCLUSIONS

Disturbed mineral metabolism according to the K/DOQI guideline is associated with more muscle and skin complaints in dialysis patients. These findings emphasize the importance of keeping mineral metabolism in dialysis patients in tight control.

We measured the plasma concentration of 1,25-dihydroxyvitamin D (1,25(OH)2D) in 39 children comprising three groups; eight with moderate renal insufficiency (GFR of 25 to 50 ml/min/1.73 M2, seven of whom had tubulointerstitial disease), eight with severe renal insufficiency (on chronic hemodialysis), and 23 healthy control subjects. The mean plasma concentration of 1,25-(OH)2D was reduced by some 40% (P less than 0.002) in the children with moderate renal insufficiency, and by some 80% (P less than 0.001) in the children with severe renal insufficiency. In the children with moderate renal insufficiency, the reduced concentration of 1,25-(OH)2D was associated with increased serum concentrations of immunoreactive parathyroid hormone (iPTH) and reduced serum concentrations of 1,25-(OH)2D was associated with increased serum concentrations of immunoreactive parathyroid hormone (iPTH) and reduced serum concentrations of calcium and phosphorus. When analyzed over the range of renal function from normal through severely impaired, values of iPTH correlate inversely and significantly with those of 1,25-(OH)2D. Growth was impaired in four of the eight children with moderate renal insufficiency. The results of the current study suggest that in children with moderate renal insufficiency, a reduction in the renal synthesis and in the plasma concentration of 1,25-(OH)2D may be important pathogenetic events in disordered metabolism of calcium and phosphorus, including secondary hyperparathyroidism.