Mineral and bone disorders including osteoporosis are common in dialysis patients and contribute to increased morbimortality. However, whether denosumab and alendronate are effective and safe treatments in hemodialysis patients is not known. Thus, we conducted a prospective, three-center study of 48 hemodialysis patients who were diagnosed as having osteoporosis and had not received anti-osteoporotic agents previously. Participants were randomized to either denosumab or intravenous alendronate, and all subjects received elemental calcium and calcitriol during the initial 2 weeks. The primary endpoint was the percent change in lumbar spine bone mineral density (LSBMD) at 12 months of treatment. The secondary endpoints included the following: change in BMD at other sites; change of serum bone turnover markers (BTM), coronary artery calcium score (CACS), ankle-brachial pressure index (ABI), brachial-ankle pulse wave velocity (baPWV), flow mediated dilation (FMD), and intima-media thickness at the carotid artery (CA-IMT); change from day 0 to day 14 in serum levels of Ca and P; time course of serum calcium (Ca), phosphorus (P), and intact parathyroid hormone (i-PTH); new fractures; and adverse events. Initial supplementation with elemental calcium and calcitriol markedly ameliorated the decrease of serum corrected calcium (cCa) levels induced by denosumab during the first 2 weeks, whereas serum cCa levels in the alendronate group were increased. Denosumab and alendronate markedly decreased serum levels of BTM and increased LSBMD at 12 months compared with baseline. However, no significant differences were found in the changes in LSBMD between the two groups. The serum cCa, P, and i-PTH levels in the two groups were maintained within the appropriate range. In contrast to the anti-osteoporotic effects, no significant differences after 12 months of treatment were found in the CACS, CA-IMT, ABI, baPWV, and FMD compared with pretreatment in both groups. Denosumab and alendronate treatment improved LSBMD, reduced BTM, and appeared to be safe in hemodialysis patients with osteoporosis. Ca ¼ calcium; P ¼ phosphate; ALP ¼ alkaline phosphatase; PTH ¼ parathyroid hormone; TRACP-5b ¼ tartrate-resistant acid phosphatase 5b; t-PINP ¼ total-type I collagen N-terminal propeptide; BAP ¼ bone-specific ALP; Hs-CRP ¼ high-sensitivity C-reactive protein; CACS ¼ coronary artery calcium score; CA-IMT ¼ intima-media thickness at the carotid artery; ABI ¼ ankle brachial pressure index; baPWV ¼ brachial-ankle pulse wave velocity; FMD ¼ flow mediated dilation.Data are presented as mean AE SD (range from 25th to75th percentile) or n (%). Journal of Bone and Mineral ResearchEFFECTS OF ANTI-OSTEOPOROTIC AGENTS IN HEMODIALYSIS PATIENTS 5 ISERI ET AL.

Abstract-We reported previously that ATP2B1 was one of the genes for hypertension receptivity in a large-scale Japanese population, which has been replicated recently in Europeans and Koreans. ATP2B1 encodes the plasma membrane calcium ATPase isoform 1, which plays a critical role in intracellular calcium homeostasis. In addition, it is suggested that ATP2B1 plays a major role in vascular smooth muscle contraction. Because the ATP2B1 knockout (KO) mouse is embryo-lethal, we generated mice with vascular smooth muscle cell-specific KO of ATP2B1 using the Cre-loxP system to clarify the relationship between ATP2B1 and hypertension. The KO mice expressed significantly lower levels of ATP2B1 mRNA and protein in the aorta compared with control mice. KO mice showed significantly higher systolic blood pressure as measured by tail-cuff method and radiotelemetric method. Similar to ATP2B1, the expression of the Na 1 In the Millennium Genome Project 2 we identified single nucleotide polymorphisms located upstream or within the ATP2B1 gene as strong susceptible polymorphisms for hypertension in Japanese. Some of these findings have been replicated in individuals of European descent in the Global Blood Pressure Genetics sample and have also been validated in other studies in individuals of European descent, 3 Koreans, 4-6 and Japanese. 7 The single nucleotide polymorphisms of ATP2B1 identified in these studies showed a significant association with hypertension in various large-scale study populations with different methods, genome-wide association study in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and the Korean study and candidate gene analysis in our previous study. However, the functional roles of ATP2B1 in blood pressure control have not yet been proven in vivo. The ATP2B1-null mutant mouse has been reported to be embryolethal 8 ; thus, we need to make a conditional knockout (KO) mouse model of ATP2B1 using the Cre-loxP system to reveal the function of the gene. Because the ATP2B1 gene encodes one of the calcium pumps and plays an important role in contraction of bladder smooth muscle, 9 we selected vascular smooth

Background. The presence of silent brain infarction (SBI) increases the risk of symptomatic stroke and dementia. The association between SBI and chronic kidney disease (CKD) has not been clarified. Moreover, little is known about what factors are related to SBI in CKD patients and whether the prevalence of SBI differs in CKD stage or cause of CKD.Methods. This is a cross-sectional study. A total of 375 subjects—335 with CKD and 40 with essential hypertension—were included. All subjects underwent magnetic resonance imaging (MRI) of the brain to detect SBI. Glomerular filtration rate (GFR) was estimated using Modification of Diet in Renal Disease equation, and cardiovascular risk factors were examined.Results. The prevalence of SBI was 56.5% in all subjects. Among causes of CKD, hypertensive nephrosclerosis had a strong association with SBI. According to the estimated GFR (eGFR) stage, the more severe the stage of eGFR, the higher the prevalence of SBI (age-adjusted odds ratio [95% confidence interval] for eGFR 30–59, 15–29 and <15 versus ≥60 mL/min/1.73 m2: 1.34 [0.68–1.99], 1.94 [1.30–2.57] and 2.51 [1.91–3.10]). In multivariate logistic analysis, eGFR was related to SBI independently, in addition to age and blood pressure (P = 0.025). However, other traditional and non-traditional risk factors were not.Conclusion. There was an independent association between eGFR and SBI. CKD patients should receive active detection of SBI and more intensive preventive management, especially for hypertension, should be needed in CKD patients to prevent SBI.

Hepatitis B virus (HBV) generates large amounts of complete and incomplete viral particles. Except for the virion, which acts as infectious particles, the function of those particles remains elusive. Extracellular vesicles (EVs) have been revealed to have biological functions. The EVs which size are less than 100 nm in diameter, were collected from HBV infected-patients. These vesicles contain, complete and incomplete virions, and exosomes, which have been recently shown to be critical as intercellular communicators. Here, the effects of the exosome, the complete, and the incomplete particles on the target cells were investigated. These particles are endocytosed by monocyte/macrophages and function primarily to upregulate PD-L1. The functions and composition of the EVs were affected by nucleotide reverse transcriptase inhibitors (NRTIs), suggesting that the EVs are involved in the pathogenesis of HBV hepatitis and clinical course of those patients treated by NRTIs.

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