Osteoblastic differentiation of bone marrow mesenchymal stem cells in uremic rats.

Severe secondary hyperparathyroidism (SHPT) represents a high turnover bone disease, osteitis fibrosa, but the pathogenesis of osteitis fibrosa remains to be fully elucidated. We examined the characteristics of the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts in uremic rats. We bred 5/6 nephrectomized (Nx) rats with a high phosphorus (P) diet to induce SHPT (Nx + HP), or Nx (Nx + ND) and normal rats (Nc + ND) fed a standard diet (ND). After 8 weeks, BMSCs were isolated from the femur and serum were analyzed. BMSCs underwent flow cytometric examination for the expression patterns of cell surface markers (CD90+, CD29+, CD45-, and CD31-). Serum creatinine (Cre) levels were significantly elevated in the Nx + NP rats compared with the Nc + NP rats. Cre levels in the Nx + HP rats were levels to those in the Nx + ND rats. Serum P and PTH levels were significantly elevated in the Nx + HP rats compared with the Nx + ND rats. Bone morphometrical analysis showed increases in both osteoid volume and eroded surfaces in the Nx + HP but not in the Nx + ND rats. The populations of harvested BMSCs were similar between all three groups. Alp, Runx2, Pth1r and Cyclin D1 mRNA expression in the BMSCs from the Nx + ND rats were significantly suppressed compared with those isolated from the Nc + ND groups. Alizarin red staining tended to be similar to the expression of these mRNA. These results suggest that the BMSCs differentiation into osteoblasts was disturbed in the uremic rats.

An examination of multiple explanations for secondary hyperparathyroidism
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AIMS: Seven theories address the evolution of secondary hyperparathyroidism (SHPT) as chronic kidney disease (CKD) progresses. The tradeoff-in-the-nephron hypothesis states that the plasma parathyroid hormone ([PTH]) concentration rises because an increased phosphate concentration in the cortical distal nephron ([P]CDN) reduces the ionized calcium concentration in that segment. In the present study, we compared this hypothesis to its predecessors. MATERIALS AND METHODS: We studied 30 patients with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73m2 (mean 29.5). To examine historic theories, we performed regressions of [PTH] on plasma concentrations of ionized calcium, phosphorus, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and fibroblast growth factor 23, and on calcium excreted per volume of filtrate (ECa/Ccr). To assess the tradeoff-in-the-nephron hypothesis, we examined regressions of [PTH] on 100/eGFR and phosphorus excreted per volume of filtrate (EP/Ccr). RESULTS: Regressions pertinent to historic theories yielded significant direct relationships between [PTH] and both ECa/Ccr and [FGF23], but neither association supported the theory to which it pertained. [PTH] varied directly with 100/eGFR and with EP/Ccr, a surrogate for [P]CDN. EP/Ccr correlated strongly with 100/eGFR. CONCLUSIONS: The only theory of SHPT that our data support is the tradeoff-in-the-nephron hypothesis. Other theories are not supported.

Impact of parathyroidectomy on left ventricular function in end stage renal disease patients.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a common complication in end-stage renal disease (ESRD) patients, and parathyroidectomy (PTX) is an effective treatment intervention of SHPT. However, the curative impact of PTX on left ventricular function still remains incompletely understood. To evaluate the impact of parathyroidectomy on left ventricular function in ESRD patients, we conducted this retrospective study. METHODS: Between Oct 1, 2010 and Oct 1, 2016, ESRD patients presented with SHPT who underwent parathyroidectomy were enrolled. We retrospectively collected the ultrasonic cardiogram parameter pre- and 1-year post-PTX, and analyzed the influence factor for the overturn of left ventricular hypertrophy (LVH) and the improvement of ejection fraction% (EF%). RESULTS: In all the patients (135), the main ultrasonic cardiogram parameter dramatically improved after PTX. Compared with pre-PTX, the left ventricular mass (LVM) (172.82 (135.90, 212.91) g vs. 192.76 (157.56, 237.97) g, p<0.001) and the left ventricular mass index (LVMI) (107.01 (86.79, 128.42) g/m2 vs. 123.54 (105.49, 146.64) g/m2, p<0.001) significantly declined after 1 year of the PTX. Further, 43.75% patients diagnosed with LVH before the PTX have recovered from LVH. In the subgroup analysis of 35 patients with EF% ≤ 60% pre-PTX, EF% and fractional shortening% (FS%) significantly improved after 1 year of the PTX compared with pre-PTX (EF%: 64.90 ± 7.90% vs. 55.71 ± 4.78%, p<0.001; FS% 35.48 ± 6.34% vs. 29.54 ± 2.88%, p<0.001), and 82.86% patients underwent an improvement of left ventricular systolic function post 1year of the PTX. CONCLUSIONS: tPTX+AT is an effective curative intervention of secondary hyperparathyroidism and can significantly overturn the LVH and increase the left ventricular systolic function.

Bone metabolism, density, and geometry in postmenopausal women with vitamin D insufficiency: a cross-sectional comparison of the effects of elevated parathyroid levels.

Increased levels of parathyroid hormone (PTH) may have adverse effects on bone health. In a cross-sectional design, we investigated this hypothesis among 102 postmenopausal vitamin D insufficient women. Elevated PTH was associated with altered bone geometry, decreased bone mineral density in the spine, and increased bone turnover. INTRODUCTION: In vitamin D insufficiency, elevated parathyroid hormone (PTH) levels may contribute to adverse effect on bone. We assessed effects of PTH responses to vitamin D insufficiency on bone metabolism, density, and geometry. METHODS: Using a cross-sectional design, we investigated 102 healthy postmenopausal women with low 25-hydroxy-vitamin D (< 50 nmol/L) levels, who had either secondary hyperparathyroidism with elevated PTH levels (> 6.9 pmol/L, N = 51) or normal PTH levels (N = 51). Bone mineral density (BMD) and bone geometry were assessed by Dual-Energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT) and high-resolution peripheral QCT (HRpQCT) scans. Bone metabolism was assessed by biochemistry including bone turnover markers. RESULTS: Levels of 25(OH)D were 38 (IQR 31-45) nmol/L with no differences between groups. PTH levels were 8.5 (IQR 7.5-9.5) in women with SHPT and 5.2 (4.4-6.6) pmol/L in women with normal PTH (p < 0.001). BMI and eGFR did not differ between groups. SHPT was associated with lower total- and trabecular bone area, lower cortical perimeter, and increased cortical area in tibia and radius. SHPT was associated with a lower weight-adjusted BMD at the lumbar spine (p < 0.05). High compared to normal PTH levels were associated with significantly lower plasma levels of 1,25(OH)2D, phosphate, but higher levels of osteocalcin and borderline higher levels of CTx. PTH correlated to osteocalcin and CTx. CONCLUSIONS: High PTH levels are associated with altered bone geometry, increased bone turnover, and reduced BMD at the spine. Whether an increased cortical thickness with a lower trabecular volume is an effect of PTH or not needs further elucidations.

Vitamin D Deficiency and Its Influence on Bone Metabolism and Density in a Brazilian Population of Healthy Men.

Vitamin D supplementation is universal for postmenopausal women, but not for elderly men, in whom osteoporosis is also commonly neglected. This study aimed to evaluate vitamin D deficiency and its association with secondary hyperparathyroidism, bone resorption, and bone density in Brazilian men. A total of 120 men, 20-93 years, were evaluated for serum calcium, phosphorus, creatinine, 25-hydroxyvitamin D (25(OH)D), parathyroid hormone, biochemical markers of bone resorption (carboxy-terminal telopeptide, carboxy-terminal peptide of type I collagen), and bone mineral density (dual-energy X-ray absorptiometry). Glomerular filtration rate (GFR) below 30 mL/min/1.73 m2, chronic diseases, and medications affecting bone were the exclusion criteria. No participant reported previous low-impact fractures. In the overall population, 25(OH)D levels were below 30 ng/mL in 46.7%, and below 20 ng/mL in 27.6%. Among the 93 patients 50 years and older, 28 had osteoporosis. In those 70 years and older, the prevalence of vitamin D deficiency (42.1%), secondary hyperparathyroidism (46.4%), high bone resorption (39.6%), decreased GFR (39.2%), and osteoporosis (41.4%) was significantly higher than in the younger subjects (p < 0.005 for all comparisons). Serum parathyroid hormone increased with aging and declining GFR, but was not significantly associated with 25(OH)D or bone mineral density. There was a clear contribution of vitamin D deficiency to increased bone resorption and osteoporosis. Binary logistic regression model considering age, 25(OH)D, and bone resorption identified age ≥70 years as the main determinant of osteoporosis. Our data demonstrate a high prevalence of vitamin D deficiency in a male population living in Rio de Janeiro, and emphasize its participation on the pathogenesis of age-related bone loss. (Vitamin D deficiency and osteoporosis are common in elderly Brazilian men.).

Epidemiology and risk factors in CKD patients with pulmonary hypertension: a retrospective study.

BACKGROUND: Pulmonary hypertension (PH) is a rare disease often associated with high mortality and is recently recognized as a common complication secondary to chronic kidney disease (CKD). Epidemiological data for this disorder across the spectrum of CKD is poorly understood. METHODS: We retrospectively analyzed 705 CKD patients with complete clinical records from July 2013 to September 2015. All the patients were estimated by echocardiography and PH was defined as pulmonary artery systolic pressure (PASP) > 35 mmHg. The prevalence of PH in CKD patients was investigated, and their association was evaluated with a logistic regression model. RESULTS: The overall prevalence of PH was 47.38%, in which mild, moderate and severe PH accounted for 22.13, 15.04 and 10.21%, respectively. The prevalence of PH in CKD stage 1-5 was 14.29, 33.33, 38.89, 40.91 and 64.47%. The prevalence of total PH was 57.63% in PD patients and 58.82% in HD patients. Compared with the non-dialysis patients, the prevalence of PH was much higher in patients receiving dialysis. Body mass index (BMI), hemoglobin, triglyceride (TG), proteinuria, parathyroid hormone (PTH) and estimated glomerular filtration rate (eGFR) were independent risk factors of PH in CKD patients. CONCLUSIONS: The prevalence of PH is increased with the deterioration of renal function, however, which has no direct relation to the severity of PH. PH occurs more frequently in dialysis patients. Higher BMI and TG, more sever anemia, proteinuria and secondary hyperparathyroidism, poor renal dysfunction predict predict the more prevalence of PH in CKD patients.

Pharmacokinetics of dexmedetomidine administered to patients with end-stage renal failure and secondary hyperparathyroidism undergoing general anaesthesia.

WHAT IS KNOWN AND OBJECTIVE: The primary objective of this study was to compare the pharmacokinetics of dexmedetomidine in patients with end-stage renal failure and secondary hyperparathyroidism with those in normal individuals. METHOD: Fifteen patients with end-stage renal failure and secondary hyperparathyroidism (Renal-failure Group) and 8 patients with normal renal and parathyroid gland function (Control Group) received intravenous 0.6 µg/kg dexmedetomidine for 10 minutes before anaesthesia induction. Arterial blood samples for plasma dexmedetomidine concentration analysis were drawn at regular intervals after the infusion was stopped. The pharmacokinetics were analysed using a nonlinear mixed-effect model with NONMEM software. The statistical significance of covariates was examined using the objective function (-2 log likelihood). In the forward inclusion and backward deletion, covariates (age, weight, sex, height, lean body mass [LBM], body surface area [BSA], body mass index [BMI], plasma albumin and grouping factor [renal failure or not]) were tested for significant effects on pharmacokinetic parameters. The validity of our population model was also evaluated using bootstrap simulations. RESULTS AND DISCUSSION: The dexmedetomidine concentration-time curves fitted best with the principles of a two-compartmental pharmacokinetic model. No covariate of systemic clearance further improved the model. The final pharmacokinetic parameter values were as follows: V1  = 60.6 L, V2  = 222 L, Cl1  = 0.825 L/min and Cl2  = 4.48 L/min. There was no influence of age, weight, sex, height, LBM, BSA, BMI, plasma albumin and grouping factor (renal failure or not) on pharmacokinetic parameters. Although the plasma albumin concentrations (35.46 ± 4.13 vs 44.10 ± 1.12 mmol/L, respectively, P < .05) and dosage of propofol were significantly lower in the Renal-failure Group than in the Control Group (81.68 ± 18.08 vs 63.07 ± 13.45 µg/kg/min, respectively, P < .05), there were no differences in the context-sensitive half-life and the revival time of anaesthesia between the 2 groups. WHAT IS NEW AND CONCLUSION: The pharmacokinetics of dexmedetomidine were best described by a two-compartment model in our study. The pharmacokinetic parameters of dexmedetomidine in patients with end-stage renal failure and hyperparathyroidism were similar to those in patients with normal renal function. Further studies of dexmedetomidine pharmacokinetics are recommended to optimize its clinical use.

A 12-week dose-escalating study of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese hemodialysis patients
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AIMS: To evaluate dose-escalation of etelcalcetide (ONO-5163/AMG 416), a novel, intravenous (IV), long-acting calcium-sensing receptor agonist, for treatment of secondary hyperparathyroidism (SHPT) in Japanese hemodialysis patients. MATERIALS AND METHODS: In this multicenter study, IV injections of etelcalcetide (3 times a week for 12 weeks) were administered, with dose escalation every 4 weeks depending on changes in serum intact parathyroid hormone (iPTH) and corrected calcium (cCa). A total of 24 patients participated in this study. RESULTS: Serum iPTH was reduced in a time- and dose-dependent manner, with reductions (in pg/mL) at 12 weeks of -226.1 ± 125.3, -362.5 ± 161.5, and -412.4 ± 130.2, respectively, for maximum doses of 5, 10, and 15 mg. At the end of the treatment, 50% of patients had serum iPTH levels within the target range (60 - 240 pg/mL). Serum cCa and phosphorus were reduced in parallel with iPTH. Adverse events (AEs) occurred in 20 patients (83.3%). The most frequently observed AEs (> 10%) were either mild or moderate nasopharyngitis (29.2%), decreased serum calcium (16.7%), and vomiting (12.5%). CONCLUSIONS: Dose-escalated triweekly etelcalcetide was effective for SHPT in Japanese hemodialysis patients and was satisfactorily tolerated.
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Effects of parathyroidectomy on bone metabolism in haemodialysis patients with secondary hyperparathyroidism.

OBJECTIVE: To evaluate the outcome of bone metabolism and bone mineral density (BMD) in haemodialysis patients after parathyroidectomy (PTX). METHODS: A total of 31 haemodialysis patients with secondary hyperparathyroidism (SHPT) were treated with PTX. BMD of lumbar spine (LS) and femoral neck (FN) was determined by dual energy X-ray absorptiometry. RESULTS: Parathyroidectomy ledds to significant decrease of serum ß-crosslaps (ß-CTX), osteocalcin (OC) and procollagen type I amino-terminal propeptide (PINP) while serum sclerostin (SOST) increased after surgery. BMD was markedly improved in both LS and FN after PTX. Z-scores analysis further confirmed that PTX significantly benefited bone metabolism in haemodialysis patients, which well correlated with the improvement of serum iPTH and OC. CONCLUSIONS: Parathyroidectomy leads to significant improvement of serum OC, PINP, ß-CTX and SOST, which may beneficially modify calcium-phosphorus metabolism and BMD in haemodialysis patients with SHPT.

We Do Too Many Parathyroidectomies for Calciphylaxis.

Calciphylaxis, a disorder of dermal arteriolar calcification with a distinct predilection for patients with advanced kidney disease, remains an enigmatic condition that challenges clinicians. Observations regarding positive associations between levels of circulating parathyroid hormone (PTH) and the risk of calciphylaxis, combined with experimental data suggesting a pathogenic role of secondary hyperparathyroidism in vascular calcification, have led to the assumption that reducing PTH levels will improve the outcomes in patients with calciphylaxis. This editorial communicates the contemporary data regarding surgical parathyroidectomy as a treatment option for these patients. We raise concerns regarding the quality of available data and discuss the direction of future comparative effectiveness research in this field.

Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial.

Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%.

[The pathophysiology of secondary hyperparathyroidism].

Secondary hyperparathyroidism (SHPT) is characterized by the acceleration of bone turnover due to the over-secretion of parathyroid hormone, which is accompanied with parathyroid hyperplasia. The pathogenesis includes the reduced production of calcitriol due to the elevated serum fibroblast growth factor 23 (FGF23) level to maintain phosphate (P) homeostasis, and its resultant hypocalcemia. Although the mechanism parathyroid glands sense P remains unknown, the expressions of calcium (Ca) sensing receptor and vitamin D receptor, which sense serum level of Ca and calcitriol respectively, down-regulate in chronic kidney disease. The rapture of feedback system including these, contributes to the development of SHPT.

[Contemporary opinions on the diagnosis and treatment of secondary hyperparathyroidism].

Secondary hyperparathyroidism is one of the most common hormonal disorders associated with a chronic kidney disease. The main causes of this disease are associated with renal failure hyperphosphatemia, hypocalcemia, and active form of vitamin D deficiency. The progressive secondary hyperparathyroidism leads to a series of complications known as a mineral and bone disorder in a chronic kidney disease. In the treatment of secondary hyperparathyroidism the most important role is played by stabilization of calcium-phosphate metabolism (through proper diet regimen, the use of phosphate binders) and reducing the synthesis and secretion of parathyroid hormone by the administration of calcimimetics and preparations of vitamin D. In the event of failure of conservative treatment complete or partial parathyroid resection should be considered.

Characteristics of hyperparathyroid states in the Canadian multicentre osteoporosis study (CaMos) and relationship to skeletal markers.

CONTEXT: PTH is an essential regulator of mineral metabolism; PTH hypersecretion may result in hyperparathyroidism including normocalcaemic, primary and secondary hyperparathyroidism. OBJECTIVE: To examine the characteristics of participants with hyperparathyroid states and the relationship to bone mineral density (BMD). DESIGN AND PARTICIPANTS: A cross-sectional study of 1872 community-dwelling men and women aged 35+ years (mostly Caucasian) with available serum PTH from Year 10 Canadian Multicentre Osteoporosis Study follow-up (2005-07). PTH was determined using a second-generation chemiluminescence immunoassay. OUTCOME MEASURES: L1-L4, femoral neck and total hip BMD. RESULTS: We established a PTH reference range (2·7-10·2 pmol/l) based on healthy participants (i.e. normal serum calcium, serum 25-hydroxyvitamin D, kidney function and body mass index, who were nonusers of antiresorptives, glucocorticoids and diuretics and not diagnosed with diabetes or thyroid disease). Participants with PTH levels in the upper reference range (5·6-10·2 pmol/l), representing a prevalence of 10·7%, had lower femoral neck and total hip BMD, by 0·030 g/cm(2) [95% confidence interval: 0·009; 0·051] and 0·025 g/cm(2) (0·001; 0·049), respectively, than those with levels 2·7-5·6 pmol/l. Participants with normocalcaemic and secondary hyperparathyroidism also had lower total hip BMD than those with levels 2·7-5·6 pmol/l, and CaMos prevalences of normocalcaemic, primary and secondary hyperparathyroidism were 3·3%, 1·4% and 5·2%, respectively. CONCLUSION: We found reduced BMD in participants with accepted hyperparathyroid states but also a notable proportion of other participants that might benefit from having lower PTH levels.

Treatment Failure of Active Vitamin D Therapy in Chronic Kidney Disease: Predictive Factors.

BACKGROUND: In patients with chronic kidney disease (CKD), impaired renal function leads to decreased vitamin D levels, which causes an increase in parathyroid hormone (PTH) production and contributes to the development of secondary hyperparathyroidism (SHPT). This may result in adverse clinical effects such as bone disorders, vascular calcification, cardiovascular disease, and increased mortality. Current treatment practices and associated outcomes with active vitamin D treatment in patients with CKD were reviewed with the objective to assess parameters (such as PTH and serum calcium levels) that may be used to define the failure of vitamin D treatment. SUMMARY: Reports based on observational data have noted improved outcomes with active vitamin D treatment (calcitriol, paricalcitol, alfacalcidol, or doxercalciferol) in patients with CKD. Criteria for the identification of active vitamin D treatment failure are unclear from current guidelines, although up to 50% of patients may experience treatment failure eventually because of development of hypercalcemia or resistant SHPT, characterized by an elevated intact PTH (iPTH) level despite treatment. We propose a definition of vitamin D treatment failure as iPTH >600 pg/ml after 6 months of intravenous active vitamin D treatment and corrected total calcium serum levels >10.2 mg/dl, and review factors that may predict the response to vitamin D treatment. Key Message: Active vitamin D treatment failure is an important challenge in clinical practice. The aim of the proposed definition is to suggest a possible framework for hypothesis generation and to encourage further research into this common problem.

Emerging drugs for secondary hyperparathyroidism.

INTRODUCTION: Secondary hyperparathyroidism (SHPT), a common, serious, and progressive complication of chronic kidney disease (CKD), is characterized by elevated serum parathyroid hormone (PTH), parathyroid gland hyperplasia, and mineral metabolism abnormalities. These disturbances may result in CKD-mineral and bone disorder (CKD-MBD), which is associated with poor quality of life and short life expectancy. AREAS COVERED: The goal of SHPT treatment is to maintain PTH, calcium, and phosphorus within accepted targeted ranges. This review highlights the pathogenesis of SHPT and current SHPT therapeutic approaches, including the use of low-phosphate diets, phosphate binders, 1,25-dihydroxyvitamin D3 (calcitriol) and its analogs, calcimimetics, and parathyroidectomy in addition to discussing emerging drugs in development for SHPT. EXPERT OPINION: Numerous studies indicate that mineral abnormalities occur early in the course of CKD, are prevalent by the time patients enter dialysis, and foreshadow a risk of cardiovascular and all-cause mortality. Several newly developed compounds may potentially overcome the limitations of current SHPT therapies. If emerging therapies can reduce PTH, normalize mineral metabolism, promote treatment adherence, and reduce the risk of side effects, they may provide the requisite features for improving long-term outcomes in patients with SHPT receiving dialysis and reduce the risks of CKD-MBD.

Control of bone resorption in mice by Schnurri-3.

Mice lacking the large zinc finger protein Schnurri-3 (Shn3) display increased bone mass, in part, attributable to augmented osteoblastic bone formation. Here, we show that in addition to regulating bone formation, Shn3 indirectly controls bone resorption by osteoclasts in vivo. Although Shn3 plays no cell-intrinsic role in osteoclasts, Shn3-deficient animals show decreased serum markers of bone turnover. Mesenchymal cells lacking Shn3 are defective in promoting osteoclastogenesis in response to selective stimuli, likely attributable to reduced expression of the key osteoclastogenic factor receptor activator of nuclear factor-κB ligand. The bone phenotype of Shn3-deficient mice becomes more pronounced with age, and mice lacking Shn3 are completely resistant to disuse osteopenia, a process that requires functional osteoclasts. Finally, selective deletion of Shn3 in the mesenchymal lineage recapitulates the high bone mass phenotype of global Shn3 KO mice, including reduced osteoclastic bone catabolism in vivo, indicating that Shn3 expression in mesenchymal cells directly controls osteoblastic bone formation and indirectly regulates osteoclastic bone resorption.

Total parathyroidectomy with autotransplantation for a rare disease derived from uremic secondary hyperparathyroidism, the uremic leontiasis ossea.

SUMMARY: We described six uremic leontiasis ossea (ULO) patients who underwent total parathyroidectomy with autotransplantation. ULO demonstrated more a systemic disease than a simple craniofacial deformation. The surgery seemed an effective treatment to alleviate secondary hyperparathyroidism and to improve patients' quality of life. ULO may have a high postoperative recurrence tendency. INTRODUCTION: ULO is a rare disease derived from uremic secondary hyperparathyroidism (SHPT). Previous studies mostly focused on the craniofacial deformations. This study aims to investigate the systemic features of the disease and the surgical outcomes. METHODS: The present study retrospectively assessed six ULO patients who underwent total parathyroidectomy (TPTX) with autotransplantation (AT). Follow-up data were recorded. The follow-up status was considered as "effectiveness" if serum intact parathyroid hormone (iPTH) levels were <150 pg/mL in the first 3 days after surgery, or as "recurrence" if serum iPTH gradually increased >300 pg/mL during follow-up in patients whose status was initially considered as "effectiveness". RESULTS: Craniofacial deformations, short stature, thoracocyllosis, spine malformations, osteodynia, and muscle weakness were observed in all patients. Abnormal pulmonary functions were observed in five patients. After surgery, one patient died from respiratory failure. Surgery was effective in the remaining five patients with relieved osteodynia and stopped craniofacial deformation. A mean follow-up of 7.6 (4 to 12) months was available. Three patients suffered from recurrence of hyperparathyroidism originating from autografts. CONCLUSIONS: Our data suggests that ULO is not only a simple disease with craniofacial malformations but is a severe systemic disease leading to increased surgical risks. TPTX with AT seems an effective treatment to relieve SHPT and to improve quality of life. ULO may have a high postoperative recurrence tendency.

Use of sevelamer to examine the role of intraluminal phosphate in the pathogenesis of secondary hyperparathyroidism.

AIMS: Parathyroid hormone (PTH) promotes calcium reabsorption in the cortical distal nephron (CDN). The phosphate concentration ([P]f) rises in that segment in chronic kidney disease (CKD); in theory, high [P]f could reduce availability of calcium for reabsorption and necessitate a compensatory rise in [PTH]. With assumptions, [P]f is proportional to phosphate excreted/volume of filtrate (EP/GFR). We therefore hypothesized that [PTH] would correlate with EP/GFR in CKD, and ΔPTH] would correlate with ΔEP/GFR after sevelamer therapy. METHODS: We conducted a 4-week, placebo-controlled trial of sevelamer carbonate in patients with CKD. [PTH]1-84 and parameters of phosphate homeostasis were measured before and after treatment. GFR was assumed to equal creatinine clearance (Ccr). Pertinent linear regressions were performed. RESULTS: Phosphate excretion fell in the sevelamer group only. Decrements in [PTH] with sevelamer differed from increments with placebo. With either treatment, [PTH] correlated with EP/Ccr and ΔPTH] correlated with ΔEP/Ccr. Changes in [PTH] were minimal in some sevelamer recipients despite reductions in EP/Ccr; calcium excreted/volume of filtrate was low in these subjects. CONCLUSIONS: Phosphate influx affected [PTH] in CKD by determining [P]f in the CDN. In some patients, low calcium influx may have blunted the effect of sevelamer on [PTH].