Increased Parathyroid Hormone Research Articles

Variación estacional de 25-hidroxi-vitamina D3, hormona paratiroidea y fosfatasa alcalina en niños escolares

El principal rol de la vitamina D es la regulación del metabolismo del calcio, cuya principal fuente es la vitamina D3 que se obtiene principalmente por la acción de la luz ultravioleta (UV) en la piel.Objetivo: Evaluar las diferencias estacionales en las concentraciones de 25-hidroxi-vitamina D3 (25OHVitD3), hormona paratiroidea (PTH), fosfatasa alcalina (FA) y calcio en niños en edad escolar.Sujetos y Método: Se midieron las concentraciones de 25OHVitD3, PTH, FA y calcio en niños de 5 a 8 años, sin suplementación de Vitamina D, reclutados en Santiago de Chile (latitud -33.4372) en distintas estaciones del año. El estatus de VitD fue definido como suficiente con concentraciones de 25OHVitD3 > 20 ng/mL (50 nmol/L), insuficiente 12-20 ng/mL (30-50 nmol/L) y deficiente < 12 ng/ mL (30 nmol/L) en base a las recomendaciones del grupo de expertos del “Consenso Global para la Prevención y Manejo del Raquitismo Nutricional”.Resultados: En total participaron 133 niños (89 prematuros menor o igual a 32 semanas), 41 durante el verano, 28 en otoño, 35 en invierno y 29 en primavera. La diferencia de las medias entre el verano y el invierno fue de 9,6 ng/mL para 25OHVitD3 (p < 0,0001), -11,1 pg/mL para PTH (p < 0,0001) y -47,5 UI/mL para FA (p = 0,01). En las concentraciones de calcio no se observaron diferencias. El 97,6% de los sujetos fueron clasificados con estatus de suficiencia (> 20 ng/mL) en verano, lo que disminuyó significativamente en invierno (54,3%, p < 0,0001).Conclusiones: Las concentraciones de 25OHVitD3 disminuyeron en aproximadamente la mitad de los niños durante el invierno, lo que se vio acompañado de un aumento de la PTH y FA, asociado a concentraciones normales de calcio. De acuerdo a nuestros resultados, la suplementación con VitD en niños podría ser necesaria durante otoño e invierno

The Effect of Aerobic Training on Parathyroid Hormone and Alkaline Phosphatase as Bone Markers in Men with Mild to Moderate Asthma

Background and Aim: Inhalation of corticosteroids in patients with asthma is associated with an increased risk of osteoporosis. This study aimed to assess the effect of aerobic training on alkaline phosphatase (ALP), parathyroid hormone (PTH) as bone biomarkers in men with mild to moderate asthma. Methods: Twenty four sedentary middle-aged men with asthma aged 40±5 years were randomly assigned to two groups as exercise (aerobic training, n=12) and control (no training, n =12). Aerobic training was performed 3 days a week for 12 weeks in the form of running on a flat surface at 60-75% of HRmax. Fasting blood samples were taken before and after the training program for measuring serum ALP and PTH. Results: There were no statistically significant differences between groups with regard to anthropometrical and bone markers at baseline (p>0.05). Aerobic training resulted in significant increase in ALP (p = 0.023) and PTH (p = 0.016) in exercise individuals. All variables remained unchanged in the control group (p>0.05). Conclusion: With an emphasis on the increase in ALP and PTH, it is concluded that relatively long-term aerobic exercise is associated with improved bone formation markers in patients with asthma treated with inhaled corticosteroids. *Corresponding Author: Mojtaba Eizadi; Email: izadim@iau-saveh.ac.ir Please cite this article as: Eizadi M, Behboudi L, Afsharmand Z. The Effect of Aerobic Training on Parathyroid Hormone and Alkaline Phosphatase as Bone Markers in Men with Mild to Moderate Asthma. Arch Med Lab Sci. 2020;6:1-9 (e20). https://doi.org/10.22037/amls.v6. 33535

Seasonal variations in 25-hydroxy vitamin D3, parathormone and alkaline phosphatase in school-aged children

The main role of Vitamin D is to regulate calcium metabolism, whose main source is vitamin D3 ob tained mostly from the action of ultraviolet (UV) light on the skin. To evaluate the seaso nal differences in the concentrations of 25-hydroxy-vitamin D3 (25OHVitD3), parathyroid hormone (PTH), alkaline phosphatase (ALP), and calcium in school-age children. The concentrations of 25OHVitD3, PTH, ALP, and calcium were measured in children from Santiago, Chile (latitude -33.4372), aged 5 to 8 years, without Vitamin D supplementation, in different seasons of the year. VitD status was defined as sufficient with concentrations of 25OHVitD3 >20 ng/mL (50 nmol/L), insufficient 12-20 ng/mL (30-50 nmol/L) and deficient <12 ng/mL (30 nmol/L) based on the recommendations of the expert group of the "Global Consensus for the Prevention and Mana gement of Nutritional Rickets". 133 children participated (89 preterms under or equal to 32 weeks), 41 during summer, 28 in fall, 35 in winter, and 29 in spring. The difference of means between summer and winter was 9.6 ng/mL for 25OHVitD3 (p <0.0001), -11.1 pg/mL for PTH (p <0.0001), and -47.5 IU/mL for ALP (p= 0.01). There were no differences in calcium concentrations. In sum mer, 97.6% of the subjects were classified with sufficiency status (> 20 ng/mL), which decreased significantly in winter to 54.3% (p <0.0001). In winter, 25OHVitD3 concentrations decreased in approximately half of the children, which was associated with an increase in PTH and ALP, and normal calcium concentrations. According to our results, children may need VitD supple mentation during fall and winter.

The effect of levetiracetam and oxcarbazepine monotherapy on thyroid hormones and bone metabolism in children with epilepsy: A prospective study

BackgroundLong-term treatment with certain antiepileptic drugs may lead to thyroid function disturbances or alterations in bone metabolism; the data on the effects of new antiepileptic drugs on this are limited and conflicting, especially in children with epilepsy. Therefore, the aim of this study was to investigate the effects of levetiracetam and oxcarbazepine on thyroid hormone levels and bone metabolism in children with epilepsy. MethodsA total of 51 children with new-onset partial epilepsy were selected. They were randomly treated with either levetiracetam (n = 25), or oxcarbazepine (n = 26) monotherapy. Eight of the 51 patients were excluded for failing to take the drug continuously or failing to undergo a regular review. Thus, 43 patients were finally included (levetiracetam: 23 patients, oxcarbazepine: 20 patients). A control group consisting of age- and sex-matched healthy subjects (n = 20) was included for comparison. Serum triiodothyronine, tetraiodothyronine, free triiodothyronine, free thyroxine, thyroid-stimulating hormone, calcium, phosphorus, alkaline phosphatase, osteocalcin, parathyroid hormone, and 25-hydroxyvitamin D levels and bone mineral density values were measured before and at 6 and 12 months after therapy in all groups. ResultsAt baseline, thyroid hormone levels, bone metabolism index, and bone mineral density values did not differ between the control group and the drug-treated groups. Levetiracetam-treated patients showed no significant changes in thyroid hormone levels, bone metabolism, and bone mineral density during the 12-month follow-up period compared with baseline values. In the oxcarbazepine group, compared to baseline values, serum free thyroxine levels decreased after 12 months of treatment (Z = −3.115, p = 0.002), and after 6 and 12 months of treatment, calcium levels decreased (Z = −3.705, p < 0.001 and Z = −3.884, p < 0.001, respectively) and parathyroid hormone levels increased (Z = −3.698, p < 0.001 and Z = −3.921, p < 0.001, respectively); however, all other parameters did not differ from baseline values. ConclusionOur data show that levetiracetam treatment has no significant effect on thyroid function and bone metabolism in children with epilepsy. Long-term use of oxcarbazepine may reduce serum free thyroxine levels, resulting in impaired thyroid function, and may reduce serum calcium and increase parathyroid hormone levels, leading to bone metabolism disorders.

Effects of cabozantinib on bone turnover markers in real-world metastatic renal cell carcinoma.

Cabozantinib strongly inhibits osteoclast differentiation and bone resorption in vitro. We aimed to evaluate its effect on bone turnover markers (BTMs) in metastatic renal cell carcinoma. This is a monocentric prospective study on patients with mRCC treated with cabozantinib between October 2016 and July 2018. We collected blood samples at baseline and after 3 and 6 months of treatment. We compared sets of data obtained from plasma samples in the whole population with unpaired 2-tailed Student t tests and data for a subset of patients for which all timepoints were available with paired 2-tailed Student t tests. We used the Kaplan-Meier method for survival analyses and the log-rank test to compare the curves. Our analysis included 39 patients. At month 3, the mean C-terminal cross-linked telopeptides of type I collagen (CTx) and the mean N-terminal propeptide of type 1 collagen (PINP) levels were significantly decreased in the whole population (p = 0.013 and p < 0.0001, respectively), as well as at paired analysis (p = 0.015 and p = 0.045, respectively). No differences were observed between baseline and 6 months (p = 0.053 and p = 0.087, respectively). After 3 months, the mean parathyroid hormone (PTH) levels significantly increased in the whole population (p = 0.004), as well as at paired analysis; the mean PTH levels increased significantly at 3 and 6 months, respectively (p = 0.019 and p = 0.041, respectively). Changes in BTM levels were not associated with outcome. Cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx and showed a transient secondary increase of PTH.

Effects of calcifediol supplementation on markers of chronic kidney disease-mineral and bone disorder in dogs with chronic kidney disease.

BackgroundChronic kidney disease‐mineral and bone disorder (CKD‐MBD) in dogs is associated with hypovitaminosis D, increased parathyroid hormone (PTH), and increased fibroblast growth factor‐23 (FGF‐23) concentrations. Best practice for vitamin D metabolite supplementation in CKD‐MBD remains unknown.ObjectiveTo provide an extended‐release calcifediol supplement to dogs with CKD and to measure its effects on variables indicative of CKD‐MBD.AnimalsTen dogs with International Renal Interest Society stages 2 and 3 CKD.MethodsIn a prospective study, dogs received a calcifediol supplement for 84 days. Serum 25‐hydroxyvitamin D (25[OH]D), 1,25‐dihydroxyvitamin D (1,25[OH]2D), 24,25‐dihydroxyvitamin D (24,25[OH]2D), creatinine, calcium, phosphorus, PTH, plasma FGF‐23 concentrations, and urine profiles were measured monthly during supplementation. Urine calcium to creatinine (UCa/Cr) ratios and fractional excretion of calcium, phosphorus, and sodium were determined.ResultsAll serum vitamin D metabolite concentrations increased significantly by day 84 (P < .001): [25(OH)D (median 249.9 ng/mL; range, 149.7‐469.9 ng/mL) compared to baseline (median 50.2 ng/mL; range, 31.3‐66.0 ng/mL); 1,25(OH)2D (median 66.1 pg/mL; range, 56.9‐88.1 pg/mL) compared to baseline (median 37.3 pg/mL; range, 29.3‐56.7 pg/mL); 24,25(OH)2D (median 81.4 ng/mL; range, 22.1‐151.7 ng/mL) compared to baseline (median 15.4 ng/mL; range, 6.9‐40.6 ng/mL)]. There were no significant differences in calcium, phosphorus, PTH concentrations, UCa/Cr or fractional excretion of calcium. No dog developed ionized hypercalcemia. Plasma FGF‐23 concentrations increased by day 84 (median 1219 pg/mL; range, 229‐8824 pg/mL) compared to baseline (median 798 pg/mL; range, 103‐4.145 pg/mL) (P < .01).Conclusions and Clinical ImportanceCalcifediol supplementation for 84 days was well‐tolerated in dogs with IRIS stages 2 and 3 CKD. It remains to be determined how long‐term supplementation would affect CKD progression and QOL.

Serotonin stimulated parathyroid hormone related protein induction in the mammary epithelia by transglutaminase-dependent serotonylation.

Mammary-derived serotonin has been implicated in breast-to-bone communication during lactation by increasing parathyroid hormone related-protein (PTHrP) in the mammary gland. It is well established that PTHrP acts on the bone to liberate calcium for milk synthesis during lactation; however, the mechanism of serotonin’s regulation of PTHrP has not been fully elucidated. Recently, serotonylation has been shown to be involved in a variety of physiological processes mediated by serotonin. Therefore, we investigated whether serotonylation is involved in serotonin’s regulation of PTHrP in the mammary gland using lactogenically differentiated mouse mammary epithelial cells. We investigated the effect of increased intracellular serotonin using the antidepressant fluoxetine or 5-hydroxytryptophan (serotonin precursor), with or without transglutaminase inhibition and the corresponding action on PTHrP induction and activity. Treatment with fluoxetine or 5-hydroxytryptophan significantly increased intracellular serotonin concentrations and subsequently increased PTHrP gene expression, which was reduced with transglutaminase inhibition. Furthermore, we determined that transglutaminase activity is increased with lactogenic differentiation and 5-hydroxytryptophan or fluoxetine treatment. We investigated whether RhoA, Rac1, and Rab4 were potential serotonylation target proteins. We speculate that RhoA is potentially a serotonylation target protein. Our data suggest that serotonin regulates PTHrP induction in part through the process of serotonylation under lactogenic conditions in mouse mammary epithelial cells.

Relationship between GFR, intact PTH, oxidized PTH, non‐oxidized PTH as well as FGF23 in patients with CKD

Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are regulators of renal phosphate excretion and vitamin D metabolism. In chronic kidney disease (CKD), circulating FGF23 and PTH concentrations progressively increase as renal function declines. Oxidation of PTH at two methionine residues (positions 8 and 18) causes a loss of function. The impact of n-oxPTH and oxPTH on FGF23 synthesis, however, and how n-oxPTH and oxPTH concentrations are affected by CKD, is yet unknown. The effects of oxidized and non-oxidized PTH 1-34 on Fgf23 gene expression were analyzed in UMR106 osteoblast-like cells. Furthermore, we investigated the relationship between n-oxPTH and oxPTH, respectively, with FGF23 in two independent patients' cohorts (620 children with CKD and 600 kidney transplant recipients). While n-oxPTH stimulated Fgf23 mRNA synthesis in vitro, oxidation of PTH in particular at Met8 led to a markedly weaker stimulation of Fgf23. The effect was even stronger when both Met8 and Met18 were oxidized. In both clinical cohorts, n-oxPTH-but not oxPTH-was significantly associated with FGF23 concentrations, independent of known confounding factors. Moreover, with progressive deterioration of kidney function, intact PTH (iPTH) and oxPTH increased substantially, whereas n-oxPTH increased only moderately. In conclusion, n-oxPTH, but not oxPTH, stimulates Fgf23 gene expression. The increase in PTH with decreasing GFR is mainly due to an increase in oxPTH in more advanced stages of CKD.

Multiple Brown Tumors Caused by Primary Hyperparathyroidism as a Differential Diagnosis to Multiple Osteolytic Bone Metastases: A Case Report

Brown tumors are benign osteolytic lesions, which usually respect the bone cortex. Since these lesions may resemble bone metastases, it is important to consider them as a potential differential diagnosis. They occur as a result of increased parathyroid hormone (PTH) secretion mainly due to primary or secondary hyperparathyroidism. We present a case of multiple osteolytic lesions incidentally found on X-ray examinations in a patient, who had a radius fracture after a low-energy trauma. Due to the suspicion of multiple bone metastases, one of them mimicking sequels after a pathological fracture in the ulna, the patient had a positron emission tomography/computed tomography (PET/CT) and a magnetic resonance imaging (MRI) scan performed supporting the existence of pervasive bone lesions without suggesting a primary malignancy. The blood samples showed highly elevated ionized calcium and PTH levels. Therefore, an ultrasound examination and parathyroid scintigraphy were performed, revealing a hyperfunctioning parathyroid adenoma. After removal of the adenoma, the PTH level normalised and the bone changes regressed without surgical intervention. J Endocrinol Metab. 2020;10(3-4):94-100 doi: https://doi.org/10.14740/jem637

Revisiting vitamin D and home-based exercises for patients with sleep apnea facing the COVID-19 quarantine.

Citation:Ekiz T, Kara M, Ozcakar L. Revisiting vitamin D and home-based exercises for patients with sleep apnea facing the COVID-19 quarantine. J Clin Sleep Med. 2020;16(8):1409–1410.

Response of Parathyroid Hormone to Vitamin D Deficiency in Otherwise Healthy Individuals.

Background and objectivesVitamin D deficiency is a global public health issue, which affects people of all ages and ethnicities. However, severe deficiency seems to be more prevalent in the Middle East and South Asia. Evidence suggests that low serum 25-hydroxycholicalciferol [25(OH)D] levels are associated with an increase in parathyroid hormone (PTH). Yet, the 25-OHD levels leading to serum PTH increase are still a matter of debate. The objective of this study is to assess deficiency of vitamin D in otherwise healthy individuals, and to determine the response of the PTH to vitamin D deficiency.MethodsThis observational study was conducted from January 2018 to May 2018. A total of 43 individuals were selected from three separate clinics in Libya (Alrazy clinic, Alhaya clinic, and Alnukbah clinic). Blood drawn from these individuals was assessed for serum calcium, phosphorus, 25(OH)D, and PTH. These data were collected and analyzed using the Statistical Package for Social Sciences (SPSS) version 17.0 for Windows (SPSS Inc., Chicago, IL).ResultsThe mean age and standard (SD) of the study participants was 47.4 ± 12.4. The age range was 19-67 years. The ratio of male to female was 1:2. The percentage of individuals with vitamin D deficiency in the study group was 95.3%, whereas the percentage of vitamin D insufficiency was 4.7%. These data suggest that individuals with severe deficiency show higher PTH values (75.66 ng/ml), whereas those with insufficiency showed lower PTH values (37.5 ng/ml).ConclusionThe population in the present study was overall deficient in 25-OH vitamin D, which indicates a greater need for supplementation with vitamin D. However, not all the individuals with vitamin D deficiency have high levels of PTH, a finding that agrees with the need for new criteria in the management of vitamin D deficiency and the importance of PTH testing.

Early biochemical response to parathyroidectomy for primary hyperparathyroidism and its predictive value for recurrent hypercalcemia and recurrent primary hyperparathyroidism

BackgroundThe traditional definition of cure after parathyroidectomy (PTX) for primary hyperparathyroidism is normocalcemia. Our hypothesis was that early postoperative levels of serum calcium and parathyroid hormone after PTX would have predictive value for later recurrence. MethodsWe performed a retrospective study of 1,146 patients with primary hyperparathyroidism who underwent PTX and had long-term biochemical follow-up. The first postoperative serum level of calcium and parathyroid hormone values were used to categorize patients into the following four early biochemical response groups: (1) complete response (normal calcium and normal parathyroid hormone), (2) partial response with hyperparathormonemia (normal calcium and increased parathyroid hormone), (3) partial response with hypercalcemia (increased calcium and normal parathyroid hormone), and (4) non-response (increases in both calcium and parathyroid hormone). Incidences of recurrent hypercalcemia and recurrent primary hyperparathyroidism >6 months after operation were then analyzed. ResultsThe overall rate of any elevated serum levels of calcium and any increase in serum levels of parathyroid hormone during >6-month follow-up was 9.8% (112 of 1146), with 6.6% (57 of 861) for group 1, 27% (35 of 129) for group 2, and 16% (20 of 127) for group 3 (P < .02). Partial biochemical responses with either increased serum calcium or increased parathyroid hormone levels were the strongest predictors of any episode of increased serum levels of calcium after 6 months and was associated with 2.7× to 4.3× the risk of recurrent primary hyperparathyroidism, respectively. ConclusionThis study demonstrates the importance of measuring parathyroid hormone in the early postoperative period to better predict later recurrent primary hyperparathyroidism.

Basal ganglia calcification in hypoparathyroidism and pseudohypoparathyroidism: local and systemic metabolic mechanisms.

Hypoparathyroidism and pseudohypoparathyroidism are rare disorders of mineral metabolism which may be associated with soft tissue calcification in the basal ganglia in the brain, and occasionally the skin and other tissues. The basal ganglia are the most common sites of calcification in the central nervous system in these disorders, and were first associated with this manifestation in a report from the Mayo Clinic in 1939. The reasons why the basal ganglia are a common site of soft tissue calcification in these rare disorders has been a matter of investigation for many years. Due to recent increased understanding of phosphate transport and new insights gained from mRNA expression in the basal ganglia, the pathophysiology of basal ganglia calcification (BGC) is now clearer. There is evidence that the absence of parathyroid hormone in hypoparathyroidism may play a direct role, but this is clearly not the case in pseudohypoparathyroidism, which is associated with increased parathyroid hormone levels. Maintaining the calcium/phosphorus ratio as close to normal as possible, and maintaining normal serum phosphate levels, may help mitigate the progression of BGC. There is no evidence of regression of BGC with conventional treatment, and long-term data with adjunctive or replacement therapy with parathyroid hormone or its analogues are not yet available. This review will focus on the pathophysiology of BGC in hypoparathyroidism and pseudohypoparathyroidism, and review the proposed pathophysiologic mechanisms, as well as the clinical implications of BGC on patient quality of life.

Association Between Plasma Intact Parathyroid Hormone Levels and the Prevalence of Atrial Fibrillation in Patients With Chronic Kidney Disease - The Fukuoka Kidney Disease Registry Study.

Parathyroid hormone (PTH) has been associated with cardiovascular disorders; however, it is unknown whether plasma PTH concentrations are associated with atrial fibrillation (AF) in patients with chronic kidney disease (CKD).Methods and Results:The present cross-sectional study analyzed baseline data of 3,384 patients registered in the Fukuoka Kidney Disease Registry Study, a Japanese multicenter prospective cohort study of patients with non-dialysis-dependent CKD. The outcome was prevalence of AF, and the main risk factor was plasma intact PTH concentration. Associations between plasma intact PTH concentration quartiles (Q1-Q4, from lowest to highest) and the presence of AF were analyzed using logistic regression. In all, 185 patients had AF; 22, 34, 59, and 70 patients were in Q1, Q2, Q3, and Q4 of PTH concentrations, respectively. The prevalence of AF increased incrementally with increases in plasma intact PTH. In the logistic regression model, patients with higher plasma intact PTH concentrations (Q2-Q4) had higher adjusted odds ratios (95% confidence intervals) for the prevalence of AF relative to the reference group (Q1), namely 1.33 (0.76-2.34), 1.82 ([1.06-3.13), and 1.99 (1.08-3.64), respectively (P=0.016). Higher plasma intact PTH concentrations were significantly and incrementally associated with an increased prevalence of AF in non-dialysis-dependent CKD patients.

Parathyroid Cell Proliferation in Secondary Hyperparathyroidism of Chronic Kidney Disease.

Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with morbidity and mortality in uremic patients. It is characterized by high serum parathyroid hormone (PTH) levels and impaired bone and mineral metabolism. The main mechanisms underlying SHP are increased PTH biosynthesis and secretion as well as increased glandular mass. The mechanisms leading to parathyroid cell proliferation in SHP are not fully understood. Reduced expressions of the receptors for calcium and vitamin D contribute to the disinhibition of parathyroid cell proliferation. Activation of transforming growth factor-α-epidermal growth factor receptor (TGF-α-EGFR), nuclear factor kappa B (NF-kB), and cyclooxygenase 2- prostaglandin E2 (Cox2-PGE2) signaling all correlate with parathyroid cell proliferation, underlining their roles in the development of SHP. In addition, the mammalian target of rapamycin (mTOR) pathway is activated in parathyroid glands of experimental SHP rats. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. Mice with parathyroid-specific deletion of all miRNAs have a muted increase in serum PTH and fail to increase parathyroid cell proliferation when challenged by CKD, suggesting that miRNA is also necessary for the development of SHP. This review summarizes the current knowledge on the mechanisms of parathyroid cell proliferation in SHP.

Комплексная оценка минерально-костных нарушений у женщин с оксалатной нефропатией в постменопаузе

A study was made of phosphorus-calcium metabolism, markers of bone metabolism, bone mineral density in 142 women in the early postmenopausal period, the patients with oxalate nephropathy at stage 2 of chronic kidney disease. It is proved that patients have signs of secondary hyperparathyroidism (hypocalcemia, hypercalciuria, increased parathyroid hormone) and a deficiency of 25 (OH) D3. Violation of bone metabolism is confirmed by a high level of β-Cross Laps and a decrease in bone mineral density. The probability of a 10-year risk of developing osteoporetic fractures in patients using the FRAX calculator is two times higher than in the control group. The conclusion was made that patients with oxalate nephropathy have a high risk of developing osteoporosis already in the early stages of chronic kidney disease.

P0690CORRELATIONS BETWEEN OPG/RANKL/RANK AXIS, VITAMIN D STATUS, PTH AND VASCULAR CALCIFICATION IN AN ADENINE-INDUCED MODEL OF CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney disease (CKD) is a major public health problem worldwide and refers to a wide range of disorders in bone and mineral metabolism, abnormalities of biochemical parameters and pathological calcification of the blood vessels. Vascular calcification (VC) is a common complication in CKD patients, contributes to cardiovascular disease (CVD), and associates with increased mortality and morbidity. The precise mechanism of VC in CKD is not yet fully understood. Recently discovered molecules such as osteoprotegerin (OPG), its ligand receptor activator of nuclear factor NF-κB ligand (RANKL) and RANK are not only well-known to play a crucial role in bone homeostasis, but they has also been implicated in the process of development of vascular complications However the exact role of OPG/RANKL/RANK axis in the process of VC has not been yet fully assessed. Thus, the aim of this work is to evaluate the role of OPG/RANKL/RANK axis in the process of calcification in CKD. Method Seventy two male Wistar rats weighing 260-290 g (8-weeks old) were initially divided into 6 groups containing 12 animals in each group. Rats were divided into six groups: control rats (K4, K6, K8) and CKD rats (B4, B6, B8). Control group rats received standard diet, whereas CKD rats were fed a low adenine – diet containing 0.3 % adenine, 1.0 % Ca, 1.2 % Pi through 4 (K4, B4), 6 (K6, B6) and 8 (K8, B8) weeks. Subsequently, CKD and control rats were sacrificed at weeks 4 (n=24), 6 (n=24) and 8 (n=24). One day before being killed, the rats were placed in metabolic cages for 24-hour urine collection. Thereafter, the rats were anesthetized and samples of blood, as well as aortas were collected. Next, the OPG, RANKL, parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxy vitamin D3 1,25(OH)2D3 concentrations were determined using appropriate ELISA kits. Then the sRANKL/OPG ratio was calculated. The OPG, RANK and RANKL gene expression was assessed using real-time PCR (RT-PCR). The VC was quantified by measurement of the arterial calcium (Ca) and phosphate (Pi) content using flame atomic absorption. Serum levels of urea nitrogen, creatinine, uric acid, Ca, Pi and urinary levels of creatinine, Ca and Pi were measured. Results There was a progressive increase in serum urea nitrogen, creatinine, uric acid and PTH of CKD rats in comparison to control values. We also observed significantly decreased levels of 25(OH)D, 1,25(OH)2D and serum Ca. Total Ca content in the aorta was significantly increased in CKD rats in comparison with control group, whereas total Pi content in the aorta was significantly increased only in B8 group in comparison to appropriate controls. There were no differences in serum OPG and sRANKL levels between CKD and control rats. In contrast, we observed decreased OPG, RANKL and RANK gene expression in a B4 group in comparison to appropriate controls, whereas in a B6 group we noticed increased OPG, RANKL and decreased RANK gene expression. B8 group revealed increased RANKL and RANK gene expression, but there were no differences in OPG gene expression between CKD rats and control group. Furthermore, we observed positive correlations between serum sRANKL and OPG and RANK gene expression. Ca and P content in the aorta inversely corelated with RANKL gene expression, whereas positively with OPG gene expression. Serum 25(OH)D concentrations correlated inversely with Ca in aorta. PTH was positively correlated with serum RANKL and OPG and gene expression these cytokines. Conclusion Our results suggest that OPG/RANK/RANKL axis may be involved in the process of vascular calcification in chronic kidney disease. However, its role and evaluation of precise mechanism in this field requires further evaluation.

P0899BIOMARKERS OF CKD-MBD IN CHILDREN

Abstract Background and Aims In recent years there has been a growth in the number of patients with chronic kidney disease (CKD). As it is known, one of the most severe complications of CKD is mineral and bone disorder (MBD). MBD, which develops in childhood, contributes not only to the development of degenerative bone disease, but also to the growth of vascular morbidity and mortality in adulthood. Therefore, adequate control of bone and mineral metabolism is one of the goals in the treatment of children with CKD. Due to the recently discovered FGF-23, a significant role in the pathogenesis of MBD is given to hyperphosphatemia as the initiator of the process. However, changes in value of phosphorus and parathyroid hormone (PTH) are revealed only on the last stages of the disease. FGF-23 is a protein, which produced in bone cells and nowadays it is considered to be the central regulator of mineral-bone metabolism. It increases the loss of phosphorus in the urine due to the blockade of the sodium-phosphorus transporter in the proximal tubule of the nephron. FGF-23 also inhibits 1α-hydroxylase and stimulates 24-hydroxylase, leading to accelerated degradation of the active form of vitamin D. Thus, the aim of our study was to investigate the relation between FGF-23 and other markers of bone metabolism such as phosphorus and parathyroid hormone. Method The study was conducted on 73 children (38 boys and 35 girls) with different stages of CKD. An average age of the patients was 9.89 ± 0.57 years. Exclusion criteria: active inflammatory, bone, infectious, oncological, immunological diseases; taking steroids and vitamin D supplements. We performed further laboratory tests: phosphorus, PTH, vitamin D and FGF-23. Serum concentration of intact FGF-23 was assessed by using the kit for ELISA method (Biomedica Medizinprodukte GmbH, Austria). This study was approved by the local scientific ethics committee of National medical university. Ethical standards and rights of patients were not violated. Descriptive statistics and correlation analysis were performed in MS Excel 2016 and SPSS 18.0. Results The laboratory tests results revealed that the mean value of phosphorus was 1.77±0.04 mmol/l among all patients with different stages of CKD. There were 29 (33.3%) children with hyperphosphatemia. The most of these patients were ESRD and they needed a renal replacement therapy. No patients with CKD 1-3 stages had high level of phosphorus. The values of PTH increase as CKD progresses. The patients with the first and second stages had absolutely normal PTH value and only 2 patients with the third stage had slightly elevated level. Only 1 out of 17 patients on dialysis (both hemodialysis and peritoneal dialysis) had an acceptable PTH value. By contrast, there was a vitamin D deficiency (a mean value was 22.4±1.64 ng/ml). The results of identification FGF-23 by the ELISA kit showed that there was also a gradual increase in its level depending on the stage of the disease. Moreover, there were 14 (19.2%) children with elevated FGF-23 concentration though other markers of bone metabolism were normal. The correlation analysis revealed positively significant associations between FGF-23 and phosphorus (r=0.60, p=0.00), FGF-23 and PTH (r=0.68, p=0.00). Conclusion Overall, our investigation proved that FGF-23 is positively correlated to phosphorus and PTH. Furthermore, in most cases, FGF-23 responds much sooner than other markers of mineral and bone metabolism and its increased value might be an early predictor of mineral and bone disorder. However, more research is required in this area.

Vitamin D in geriatric patients

VitaminD deficiency is widespread in geriatric patients. While vitaminD deficiency is prevalent in about 50% of healthy older adults, the prevalence in geriatric patients with hip fracture increases to over 80%. This is partly due to the fact that sunlight is unreliable as the main source of vitaminD. In addition to insufficient sun intensity from November to April, skin aging plays an important role; it causes a4-fold reduction in the skin's own vitaminD production during sunshine exposure in older adults compared with younger people. Immobility and institutionalization are additional risk factors for vitaminD deficiency in geriatric patients. At the same time, vitaminD deficiency (< 20 ng/ml) increases parathyroid hormone levels and thus promotes bone loss and the risk of fracture. Severe vitaminD deficiency (< 10 ng/ml) may also lead to reversible muscle weakness resulting in an increased risk of falling. Since falls affect at least every second geriatric patient and hip fractures increase exponentially after the age of 75, the correction of vitaminD deficiency is an important medical and public health effort in these patients. Several randomized intervention trials, comparing 800-1000 IU vitaminD/day versus placebo or calcium, showed asignificant reduction in falls and hip fractures in adults ≥65years of age who had an increased risk of vitaminD deficiency and of falls or fractures. In geriatric patients, implementing vitaminD supplementation at this dosage is currently preferred. Abolus dose of over 24,000 IU/month should be avoided due to the increased risk of falls and fractures. These recommendations remain relevant after acritical review of the four most recent meta-analyses.

Effects of parathyroid hormone and vitamin D supplementation on stroke among patients receiving peritoneal dialysis

BackgroundContinuous ambulatory peritoneal dialysis (CAPD) patients have a high incidence of stroke and commonly have increased parathyroid hormone levels and vitamin D insufficiency. We seek to investigate the incidence of stroke and the role of parathyroid hormone and vitamin D supplementation in stroke risk among CAPD patients.MethodsThis study employed a retrospective design. We enrolled a Chinese cohort of 980 CAPD patients who were routinely followed in our department. The demographic and clinical data were recorded at the time of initial CAPD and during follow-up. The included patients were separated into non-stroke and stroke groups. The effects of parathyroid hormone and vitamin D supplementation on stroke in CAPD patients was evaluated. The primary endpoint is defined as the first occurrence of stroke, and composite endpoint events are defined as death or switch to hemodialysis during follow-up.ResultsA total of 757 eligible CAPD patients with a mean follow-up time of 54.7 (standard deviation, 33) months were included in the study. The median incidence of stroke among our CAPD patients was 18.9 (interquartile range, 15.7–22.1) per 1000 person-years. A significant nonlinear correlation between baseline iPTH and hazard of stroke (p-value of linear association = 0.2 and nonlinear association = 0.002) was observed in our univariate Cox regression analysis, and low baseline iPTH levels (≤150 pg/ml) were associated with an increased cumulative hazard of stroke. Multivariate Cox regression analysis indicated a significant interaction effect between age and iPTH after adjusting for other confounders. Vitamin D supplementation during follow-up was a predictive factor for stroke in our cohort.ConclusionsCAPD patients suffered a high risk of stroke, and lower iPTH levels were significantly correlated with an increased risk of stroke. Nevertheless, vitamin D supplementation may reduce the risk of stroke in these patients.