Associations of cardiovascular disease and blood pressure with cognition in hemodialysis patients: The Osaka Dialysis Complication Study.

BACKGROUND: Previous studies have reported mixed results regarding the contributions of cardiovascular disease (CVD) and blood pressure (BP) to cognitive impairment in chronic kidney disease. METHODS: This was a cross-sectional study in 1213 patients on maintenance hemodialysis from 17 dialysis units in Japan. The main exposures were prior CVD and BP components including systolic BP (SBP) and diastolic BP (DBP). The outcome was low cognitive function evaluated with the Modified Mini-Mental State (3MS) examination with a cut-off level of 3MS <80. RESULTS: The median age was 67 years, median duration of dialysis was 71 months, 37% were women, 39% had diabetic kidney disease and 36% had any pre-existing CVD. Median (interquartile range) of 3MS score was 91 (82-97), and 240 patients (20%) had 3MS <80. Logistic regression analysis showed that 3MS <80 was associated with the presence of any prior CVD, particularly prior stroke. 3MS <80 was associated with lower DBP but not with SBP. When patients were stratified by the presence of prior stroke, lower DBP, higher age and lower education level were factors associated with 3MS <80 in both subgroups. In the subgroup of patients without prior stroke, diabetic kidney disease was an additional factor associated with 3MS <80. CVDs other than stroke were not associated with 3MS in either subgroup. CONCLUSIONS: Prior stroke and lower DBP were associated with 3MS <80 in hemodialysis patients. These findings support the hypothesis that these vascular factors contribute to low cognitive performance in patients undergoing hemodialysis.

Bexarotene-induced central hypothyroidism assessed by TRH stimulation test in cutaneous T-cell lymphoma patients.

Bexarotene-induced central hypothyroidism (CH), for which levothyroxine (LT4) replacement is recommended, has been shown to be caused by pituitary but not hypothalamic disorder experimentally, though the underlying mechanism in humans remains unclear. Here, the pathophysiology of bexarotene-induced CH was examined using a TRH stimulation test in cutaneous T-cell lymphoma (CTCL) patients. In this retrospective longitudinal observational study, serum TSH and free T4 (F-T4) levels were measured in 10 euthyroid patients with CTCL during 24 weeks of bexarotene treatment. TRH stimulation testing was performed following CH diagnosis, with LT4 replacement dosage adjusted to maintain F-T4 at the pre-treatment level. After one week of bexarotene administration, all 10 patients developed CH, based on combined findings of low or low-normal F-T4 with low or normal TSH levels. TSH peak response after a stimulation test at one week was reached at 30 minutes. However, that was <4 µIU/mL in all patients, indicating a blunted though not exaggerated and delayed TSH response. In eight who continued bexarotene for 24 weeks, median LT4 replacement dosage was 125 (range, 75-150) µg/day. TSH level at 30 as well as 15, 60, 90, and 120 minutes after TRH stimulation was significantly correlated with LT4 replacement dosage (ρ = -0.913, p = 0.002), whereas TSH and F-T4 basal levels at one week were not. These results suggest that pituitary hypothyroidism is responsible for bexarotene-induced CH, while TSH levels after TRH stimulation precisely reflect residual pituitary-thyroid function in patients receiving bexarotene.

Role of adiponectin in the relationship between visceral adiposity and fibroblast growth factor 23 in non-diabetic men with normal kidney function.

Fibroblast growth factor 23 (FGF23) is a key regulator of phosphate metabolism. Circulating FGF23 levels are associated with obesity, metabolic syndrome, and cardiovascular disease in the general population, but the underlying mechanism remains unclear. Therefore, we aimed to determine the associations between serum FGF23 levels and visceral adiposity as well as serum adiponectin levels in 189 adults without diabetes and with normal kidney function who were selected from the MedCity21 health examination registry. The exclusion criteria included diabetes mellitus or impaired kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). Levels of serum FGF23 and total adiponectin, and visceral fat area (VFA) on computed tomography images were measured. Serum FGF23 levels were higher and VFA was greater, whereas serum adiponectin levels were lower in men than in women. Serum FGF23 levels positively correlated with VFA in men; they remained marginally significant after adjusting for age, eGFR, and serum levels of calcium, phosphate, intact parathyroid hormone, and 1,25-dihydroxyvitamin D. Importantly, when serum adiponectin levels were included as a covariate, serum adiponectin levels comprised an independent determinant of serum FGF23 levels in men, whereas VFA did not. In conclusion, lower serum adiponectin, rather than a greater VFA, was associated with higher serum FGF23 levels in non-diabetic men with normal kidney function. These findings suggest that adiponectin plays a role in the relationship between visceral adiposity and FGF23 in men.

Fibroblast Growth Factor 23 as Regulator of Vitamin D Metabolism.

Fibroblast growth factor 23 (FGF23) is a hormone produced by osteocytes in bone that acts on the kidneys to regulate phosphate and vitamin D metabolism.FGF23 levels were shown to be increased in the early stage of chronic kidney disease (CKD), with a slight decline in estimated glomerular filtration rate (eGFR) even when the range was restricted to above 60 mL/min/1.73 m2, indicating that subtle phosphate load is a stimulator of FGF23 in serum. FGF23 is also known to inhibit vitamin D activation from 25-hydroxyvitamin D (25-OH-D) to 1,25-dihydroxyvitamin D [1,25(OH)2D], while it stimulates its degradation from 25-OH-D to 24,25-dihydroxyvitamin D [24,25(OH)2D]. Previously, we demonstrated a significant and negative association of serum FGF23 with serum 1,25(OH)2D and 1,25(OH)2D/25-OH-D ratio, a putative parameter for CYP27B1, and confirmed the physiological effects of FGF23 on phosphate and vitamin D metabolism in non-CKD subjects. Elevated FGF23 by itself is reported to be associated with various adverse outcomes, including left ventricular hypertrophy, endothelial dysfunction, and activation of the renin-angiotensin-aldosterone system, leading to increased mortality even in non-CKD individuals. On the other hand, our previous study showed that the impaired incremental response of serum FGF23 in response to oral phosphate load in diabetic patients can help to significantly increase serum phosphate (Yoda et al., J Clin Endocrinol Metab 97:E2036-43, 2012) and thus may contribute to progression of vascular calcification in those patients (personal observation). It is suggested that increased serum FGF23 might be an important indicator of adverse outcomes in non-CKD as well as CKD patients.

Significant Association of Diabetes With Mortality of Chronic Hemodialysis Patients, Independent of the Presence of Obesity, Sarcopenia, and Sarcopenic Obesity.

OBJECTIVES: This retrospective cohort study investigated the association of diabetes with mortality in hemodialysis patients with regard to obesity, sarcopenia, and sarcopenic obesity, along with examining the prevalence of each group and diabetes. METHODS: Muscle strength, muscle mass, and fat mass were evaluated using a hand dynamometer and dual-energy X-ray absorptiometry, respectively, in 308 chronic hemodialysis patients (age 58.0 ± 11.9 years, hemodialysis duration 6.5 ± 6.0 years, males 60.1%, diabetes 32.8%). Sarcopenia was defined according to the new criteria established by the Asian Working Group on Sarcopenia 2019. Obesity was defined by percent body fat mass (males ≥25%, females ≥35%). RESULTS: The enrolled patients were divided into the normal (38.7%), obesity (18.8%), sarcopenia (26.9%), and sarcopenic obesity (15.6%) groups. The prevalence of diabetes was significantly skewed among the 4 groups (χ2 test, P = .0057), being higher in the sarcopenic obesity group (54.2%) compared to the others (25.9-33.7%). Multivariate regression analysis revealed that diabetes was significantly and independently associated with sarcopenic obesity (odds ratio 3.495, 95% confidence interval 1.683-7.255, P = .0008) after adjustments for several cofounders, but not significantly associated with sarcopenia. During the follow-up period of 76 ± 35 months, 100 patients died. Those in the sarcopenia and sarcopenic obesity groups had significantly higher rates of all-cause mortality compared to patients in the normal and obesity groups (P = .0004, log-rank test). Furthermore, multivariate Cox proportional hazards analysis revealed that presence of diabetes was significantly associated with higher all-cause mortality in all 308 patients, after adjustments for several factors, including the presence of each group in 4 models. CONCLUSION: Sarcopenic obesity is highly prevalent in chronic hemodialysis patients. Diabetes was found to be a significant and independent contributor to the presence of sarcopenic obesity. Diabetes was shown to be a significant predictor of all-cause mortality, independent of the present normal, obesity, sarcopenia, and sarcopenic obesity groups.

Efficacy of romosozumab in patients with osteoporosis on maintenance hemodialysis in Japan; an observational study.

INTRODUCTION: Romosozumab reportedly increases bone mineral density (BMD) potently but might adversely affect cardiovascular disease (CVD). We evaluated the efficacy of romosozumab in osteoporotic HD patients with a high risk of fracture. MATERIALS AND METHODS: This was a single-center 1-year study in Japanese HD patients. Among 96 HD romosozumab-treated HD patients with high risk of fracture, 76 HD patients completed 1 year of subcutaneous administration of romosozumab (210 mg/4 weeks) for 1 year. Romosozumab-untreated HD patients (n = 55) were also included. Changes in BMD and serum markers, together with fracture occurrence, and CVD events, were monitored. RESULTS: During romosozumab treatment of 76 HD patients, BMD time-dependently increased significantly by 15.3% ± 12.9% at the lumbar spine (L1-4), and 7.2% ± 8.3% at the femoral neck at 1 year. Serum BAP and total P1NP increased significantly and serum TRACP-5b decreased at 4 weeks. Fragility fractures occurred in three (3.8%) patients. Hypocalcemia occurred at 4-48 weeks despite the increased dosing of active vitamin-D derivatives, but without any symptom. New CVD events occurred in 5.2% of romosozumab-treated HD patients and10.9% in romosozumab-untreated HD patients. CONCLUSIONS: BMD was increased significantly during romosozumab treatment at the lumbar spine, and the femoral neck, respectively, at 1 year in HD patients. Hypocalcemia occurred but without any intolerable event. There was no apparent increase in CVD events during 1 year of study, suggesting romosozumab as a promising agent for HD patients with severe osteoporosis.

Etelcalcetide decreases the PTH-calcium setpoint without changing maximum and minimum PTH secretion in mice with primary hyperparathyroidism.

INTRODUCTION: Etelcalcetide binds to the extracellular domain of the calcium-sensing receptor (CaSR), while cinacalcet binds to the 7-transmembrane domain of the CaSR; however, it is unknown, whether etelcalcetide has similar effects to cinacalcet on parathyroid hormone (PTH) secretion. MATERIALS AND METHODS: The PTH-calcium setpoint and maximum and minimum PTH secretion were determined using an 'in vivo setpoint analyses.' The PTH-calcium setpoint was obtained in a mouse model of primary hyperparathyroidism (PC) and wild-type (WT) mice, with PC mice divided into two groups. The setpoint was obtained after 7 days of etelcalcetide (3.0 mg/kg BW/day) or vehicle administration via anosmotic pump. After 7 days of crossover administration, the setpoint was obtained again. Parathyroid glands were obtained after crossover administration, and CaSR expression was analyzed by immunohistochemistry. RESULTS: Etelcalcetide administration significantly decreased the setpoint from 9.03 ± 0.56 mg/dL to 6.80 ± 0.28 mg/dL, which was restored to 8.81 ± 0.38 mg/dL after vehicle administration. In the second group of mice, vehicle administration did not alter the setpoint (8.84 ± 0.69 mg/dL to 8.98 ± 0.63 mg/dL), but subsequent etelcalcetide administration significantly decreased it to 7.10 ± 0.72 mg/dL. There was no significant change in maximum and minimum PTH secretion. Expression levels of parathyroid CaSR were lower in PC mice than in WT mice; however, no significant differences were observed between the two mouse groups. CONCLUSION: Etelcalcetide decreased the PTH-calcium setpoint without changing maximum and minimum PTH secretion in PC mice, suggesting that like cinacalcet, etelcalcetide has calcimimetic potency.

Effect of etelcalcetide on parathyroid hormone secretion by primary hyperparathyroidism patient-derived primary parathyroid cells.

INTRODUCTION: Etelcalcetide (Parsabiv®, AMG 416/ONO-5163) is a novel allosteric modulator for the calcium-sensing receptor approved for hemodialysis patients with secondary hyperparathyroidism of uremia. Etelcalcetide reduced parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism of uremia in clinical studies. However, its direct effect on parathyroid hormone secretion in human parathyroid cells remains unknown. This study aimed to determine if etelcalcetide suppresses parathyroid hormone secretion by human parathyroid cells in vitro. MATERIALS AND METHODS: We prepared primary cell cultures from human parathyroid tissue and determined calcium-sensing receptor expression levels by immunohistochemistry. Pathyroid tumors were removed from fourteen patients with primary hyperparathyrodism. Parathyroid tissue was dispersed with collagenase, resuspended in culture medium, incubated for 2 h with etelcalcetide and Ca2+, and the medium was then collected. Final etelcalcetide concentrations in the medium were 0.005-50 µmol/L. Levels of human parathyroid hormone in the medium were determined by enzyme-linked immunosorbent assay. RESULTS: In eight of the fourteen parathyroid cell cultures, extracellular Ca2+ reduced parathyroid hormone levels. In four of the eight parathyroid cell cultures which responded extracellular Ca2+, etelcalcetide reduced hormone secretion with the 50% effective concentrations of 0.57, 20.8, 0.42, and 0.57 µmol/L. Expression levels of the calcium-sensing receptor were significantly lower in primary hyperparathyroidism patient-derived parathyroid tissues compared with controls. CONCLUSION: This is the first report that etelcalcetide directly reduced parathyroid hormone secretion from the primary cultured human parathyroid cells from patients with primary hyperparathyroidism. To verify this conclusion, further studies are needed using secondary hyperparathyroidism patient-derived parathyroid cells.

Evaluation of myostatin as a possible regulator and marker of skeletal muscle-cortical bone interaction in adults.

INTRODUCTION: Bone mass was recently reported to be related to skeletal muscle mass in humans, and a decrease in cortical bone is a risk factor for osteoporosis. Because circulating myostatin is a factor that primarily controls muscle metabolism, this study examined the role of myostatin in bone mass-skeletal muscle mass interactions. METHODS: The subjects were 375 middle-aged community residents with no history of osteoporosis or sarcopenia who participated in a health check-up. Cortical bone thickness and cancellous bone density were measured by ultrasonic bone densitometry in a health check-up survey. The subjects were divided into those with low cortical bone thickness (LCT) or low cancellous bone density (LBD) and those with normal values (NCT/NBD). Bone metabolism markers (TRACP-5b, etc.), skeletal muscle mass, serum myostatin levels, and lifestyle were then compared between the groups. RESULTS: The percentage of diabetic participants, TRACP-5b, and myostatin levels were significantly higher, and the frequency of physical activity, skeletal muscle mass, grip strength, and leg strength were significantly lower in the LCT group than in the NCT group. The odds ratio (OR) of high myostatin levels in the LCT group compared with the NCT group was significant (OR 2.17) even after adjusting for related factors. Between the low cancellous bone density (LBD) and normal cancellous bone density (NBD) groups, significant differences were observed in the same items as between the LCT and NCT groups, but no significant differences were observed in skeletal muscle mass and blood myostatin levels. The myostatin level was significantly negatively correlated with cortical bone thickness and skeletal muscle mass. CONCLUSIONS: A decrease in cortical bone thickness was associated with a decrease in skeletal muscle mass accompanied by an increase in the blood myostatin level. Blood myostatin may regulate the bone-skeletal muscle relationship and serve as a surrogate marker of bone metabolism, potentially linking muscle mass to bone structure.

Plasma Xanthine Oxidoreductase Activity Associated with Glycemic Control in Patients with Pre-Dialysis Chronic Kidney Disease.

INTRODUCTION: Xanthine oxidoreductase (XOR) activity plays an important role as a pivotal source of reactive oxygen species, which is associated with cardiovascular disease (CVD) events. Patients with CKD have increased risk of CVD events. In the present study, factors associated with plasma XOR activity in pre-dialysis CKD patients were investigated. METHODS: In this cross-sectional study, plasma XOR activity in 118 pre-dialysis CKD patients (age 68 [57-75] years; 64 males, 26 with diabetes mellitus [DM]) was determined using a newly established highly sensitive assay based on (13C2,15N2) xanthine and liquid chromatography/triple quadrupole mass spectrometry. RESULTS: Plasma glucose, hemoglobin A1c, and estimated glomerular filtration (eGFR) were significantly and positively correlated with plasma logarithmically transformed XOR (ln-XOR) activity. In multiple regression analyses, eGFR and hemoglobin A1c or plasma glucose were significantly, independently, and positively associated with plasma ln-XOR activity after adjusting for several confounders. Plasma XOR activity was significantly higher in CKD patients with (n = 26) than in those without (n = 92) DM (62.7 [32.3-122] vs. 25.7 [13.4-45.8] pmol/h/mL, p < 0.001). A total of 38 patients were taking uric acid-lowering drugs. Multiple regression analysis of CKD patients not administered uric acid-lowering drugs (n = 80) showed no significant association between eGFR and plasma ln-XOR activity. In contrast, association between glycemic control and plasma ln-XOR activity was significant even in CKD patients without uric acid-lowering drug treatment. CONCLUSIONS: These results indicate the importance of glycemic control in CKD patients in regard to decreased XOR, possibly leading to a decrease in CVD events.

Clinical and histopathological features of acute kidney injury in adult-onset minimal change nephrotic syndrome.

BACKGROUND: Acute kidney injury (AKI) is a common complication of minimal change nephrotic syndrome (MCNS), particularly in adults. To predict development of AKI, as defined by the Kidney Disease Improving Global Outcomes classification, we investigated clinical and histopathological features of adult-onset MCNS patients. METHODS: A retrospective study was conducted with biopsy-proven adult-onset MCNS patients treated with corticosteroids. RESULTS: A total of 58 MCNS patients [49 (24-71) years old, 38 males] were diagnosed using kidney biopsy findings from 2005 to 2018 at Osaka City University Hospital, of whom 24 (41.4%) were found to be complicated with AKI. Age, urinary protein, increased body weight (difference from admission to discharge), and histopathological scores were significantly greater in patients with as compared to without AKI, while urinary protein, increased body weight, and interstitial edema score were significantly associated with AKI development [OR 1.55 (95% CI 1.04-2.31), 1.37 (95% CI 1.03-1.81), 20.7 (95% CI 1.76-243), respectively]. Of the 24 MCNS patients with AKI, 10 underwent transient hemodialysis treatment. Although histopathological features were not different, the time interval between disease onset and kidney biopsy was significantly longer for MCNS patients complicated with AKI requiring hemodialysis as compared to those for whom that was not required [32 (24-46) vs. 13 (10-23) days, p = 0.034]. CONCLUSION: These results indicate that urinary protein, increased body weight, and interstitial edema score are important information for predicting development of AKI in adult-onset MCNS patients.

JNK and ATF4 as two important platforms for tumor necrosis factor-α-stimulated shedding of receptor for advanced glycation end products.

Soluble receptor for advanced glycation end products (sRAGE), shed from cell surfaces, is found in human circulation and has been implicated in cardiovascular disease. Its pathophysiological regulation and underlying mechanisms are scarcely understood. In endothelium-specific human RAGE transgenic mice, human sRAGE was detected in circulation, whereas its level was markedly increased after LPS treatment. That increase was preceded by a rapid rise in TNF-α level. Treatment with TNF-α also significantly increased serum sRAGE. In human microvascular endothelial cells or human umbilical vein endothelial cells with RAGE overexpression, TNF-α markedly induced RAGE shedding, which was dependent on MMP9 and ADAM10. TNF-α-stimulated MMP9 expression was completely dependent on JNK activation, with its inhibition partially effective in suppressing TNF-α-induced RAGE shedding. In contrast, TNF-α transiently induced activation transcription factor (ATF)4, a major component in unfolded protein response (UPR), whereas knockdown of ATF4 abrogated TNF-α-stimulated RAGE shedding. Protein levels of the pro and activated forms of ADAM10 were also decreased by ATF4 knockdown, whereas inhibition of other components of UPR, including XBP1 and ATF6, failed to block TNF-α-stimulated RAGE shedding. Although the endoplasmic reticulum stressors thapsigargin and tunicamycin induced markedly and sustained expression of ATF4 and XBP-1, they did not induce RAGE shedding to the same level as TNF-α, suggesting that ATF4 is necessary but not sufficient alone for TNF-α-mediated RAGE shedding. ATF4 inhibition did not affect TNF-α-stimulated MMP9 expression, whereas inhibition of JNK activity did not influence ADAM10 activation. Thus, inflammatory cascades including TNF-α induced RAGE shedding in endothelial cells in vivo and in vitro. JNK and ATF4 may be 2 platforms for regulation of TNF-α-stimulated RAGE shedding.-Miyoshi, A., Koyama, S., Sasagawa-Monden, M., Kadoya, M., Konishi, K., Shoji, T., Inaba, M., Yamamoto, Y., Koyama, H. JNK and ATF4 as two important platforms for tumor necrosis factor-α-stimulated shedding of receptor for advanced glycation end products.

Bazedoxifene improves renal function and increases renal phosphate excretion in patients with postmenopausal osteoporosis.

INTRODUCTION: Because aging is a predictor of renal insufficiency in the general population, renal function is a concern in postmenopausal patients undergoing treatment for osteoporosis. Although high serum phosphate concentration is a predictor of renal insufficiency, the effect of selective estrogen receptor modulator (SERM) on renal function and phosphate homeostasis remains to be established. MATERIALS AND METHODS: We administered 20 mg/day bazedoxifene to 48 postmenopausal osteoporotic women who had been taking alfacalcidol for ≥ 6 months, and assessed lumbar spine bone mineral density (LS-BMD), renal function (by calculating estimated glomerular filtration rate using serum cystatin-C levels [eGFRcys] [range 38.0-98.2 mL/min/1.73 m2]), and phosphate homeostasis. RESULTS: LS-BMD was significantly higher 6 months after the initiation of bazedoxifene administration. eGFRcys had increased by 3 months after initiation and was stable until 12 months. Serum phosphate gradually decreased after initiation, reaching statistical significance at 6 months. The changes in serum phosphate were also significant when the maximum tubular reabsorption rate of phosphate was normalized to glomerular filtration rate (TmP/GFR), indicating that bazedoxifene treatment reduces serum phosphate by increasing the urinary excretion of phosphate. The change in eGFRcys after the initiation of bazedoxifene was significantly negatively correlated with the change in serum phosphate, suggesting that a reduction in serum phosphate improves renal function. CONCLUSION: Bazedoxifene improves renal function, possibly by increasing renal phosphate excretion, in postmenopausal osteoporotic women without severe renal insufficiency.

Executive summary of clinical practice guide on fracture risk in lifestyle diseases.

Accumulating evidence has shown that patients with lifestyle diseases such as type 2 diabetes mellitus, chronic kidney disease, and chronic obstructive pulmonary disease are at increased risk of osteoporotic fracture. Fractures deteriorate quality of life, activities of daily living, and mortality as well as a lifestyle disease. Therefore, preventing fracture is an important issue for those patients. Although the mechanism of the lifestyle diseases-induced bone fragility is still unclear, not only bone mineral density (BMD) reduction but also bone quality deterioration are involved in it. Because fracture predictive ability of BMD and FRAX® is limited, especially for patients with lifestyle diseases, the optimal management strategy should be established. Thus, when the intervention of the lifestyle diseases-induced bone fragility is initiated, the deterioration of bone quality should be taken into account. We here review the association between lifestyle diseases and fracture risk and proposed an algorism of starting anti-osteoporosis drugs for patients with lifestyle diseases.

Independent association of plasma xanthine oxidoreductase activity with serum uric acid level based on stable isotope-labeled xanthine and liquid chromatography/triple quadrupole mass spectrometry: MedCity21 health examination registry.

Background We developed a novel high-sensitive assay for plasma xanthine oxidoreductase (XOR) activity that is not affected by the original serum uric acid level. However, the association of plasma XOR activity with that level has not been fully examined. Methods This cross-sectional study included 191 subjects (91 males, 100 females) registered in the MedCity21 health examination registry. Plasma XOR activity was determined using our assay for plasma XOR activity with [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. Serum levels of uric acid and adiponectin, and visceral fat area (VFA) obtained by computed tomography were measured, and insulin resistance was determined based on the homeostasis model assessment (HOMA-IR) index. Results The median values for uric acid and plasma XOR activity were 333 µmol/L and 26.1 pmol/h/mL, respectively. Multivariable linear regression analysis showed a significant and positive association of serum uric acid level (coefficient: 26.503; 95% confidence interval: 2.06, 50.945; p = 0.035) with plasma XOR activity independent of VFA and HOMA-IR, and also age, gender, alcohol drinking habit, systolic blood pressure, estimated glomerular filtration rate (eGFR), glycated hemoglobin A1c, triglyceride, and adiponectin levels. The "gender*XOR activity" interaction was not significant (p = 0.91), providing no evidence that gender modifies the relationship between plasma XOR activity and serum uric acid level. Conclusions Plasma XOR activity was found to be positively associated with serum uric acid level independent of other known confounding factors affecting that level, including gender difference, eGFR, adiponectin level, VFA, and HOMA-IR.

Association of higher arterial ketone body ratio (acetoacetate/ß-hydroxybutyrate) with relevant nutritional marker in hemodialysis patients.

BACKGROUND: An association of higher levels of ß-hydroxybutyrate (ß-HB) in serum with greater mortality in hemodialysis (HD) patients has been reported. This study examined the significance of arterial ketone body ratio (AcAc/ß-HB), a relevant marker of energy state, in HD patients. METHODS: The levels of arterial AcAc and ß-HB, and AcAc/ß-HB ratio were determined in 49 HD patients just before undergoing an HD session. Additionally, changes in those levels during the session were examined to investigate their associations with clinical nutritional markers. RESULTS: Arterial ß-HB, but not AcAc, was significantly higher at the baseline in 25 patients with type 2 diabetes mellitus (T2DM) as compared to 24 non-DM patients, with a significant reduction in arterial AcAc/ß-HB ratio seen in those with DM. Although the arterial AcAc/ß-HB ratio before the HD session was significantly higher in the non-DM group, it did not differ significantly after the session between the groups, indicating a faster rate of ß-HB disappearance from circulation in non-DM HD patients during the interdialytic period. Multiple regression analysis, which included age, gender, presence/absence of DM, log HD duration, log ß-HB, and log AcAc/ß-HB ratio as independent variables, revealed an independent and significant association of log AcAc/ ß-HB ratio, but not log ß-HB, with serum albumin and uric acid. CONCLUSION: We found that a decreased AcAc/ß-HB ratio resulting from increased ß-HB, but not increased ß-HB itself, was a significant factor independently associated with decreased levels of serum albumin and uric acid, known to be related to higher mortality in HD patients. Furthermore, it is possible that higher mortality in DM HD patients can be explained by reduced arterial AcAc/ß-HB ratio.

Oncostatin M induces C2C12 myotube atrophy by modulating muscle differentiation and degradation.

Oncostatin M (OSM) is a cytokine of the interleukin-6 family and plays a role in various disorders such as cancer and inflammatory diseases, which are often accompanied by skeletal muscle atrophy, or sarcopenia. However, the role of OSM in the regulation of skeletal muscle mass remains to be identified. In this study, we investigated the effect of OSM on C2C12 myotube formation in vitro. C2C12 myoblasts were induced to differentiate into myotubes for 3 days and then treated with OSM for 24 or 48 h. The diameter of differentiated C2C12 myotubes were reduced by 18.7% and 23.3% compared to control cells after treatment with OSM for 24 and 48 h, respectively. The expression levels of MyoD and myogenin were decreased, while those of atrogin-1, CCAAT/enhancer binding protein δ, and OSM receptor were increased in C2C12 myotubes treated with OSM for 24 h compared to control cells. Furthermore, the inhibitory effect of OSM on myotube formation was significantly attenuated by pretreatment with an inhibitor of signal transducer and activator of transcription (STAT) 3 or by knockdown of Stat3. Finally, the OSM-induced changes in the expression levels of MyoD, myogenin, and atrogin-1 were reversed by pretreatment with an inhibitor of STAT3 or by Stat3 knockdown in C2C12 myotubes. In conclusion, OSM induces C2C12 myotube atrophy by inhibiting myogenic differentiation and activating muscle degradation in a STAT3-dependent manner.

Plasma omentin levels are inversely associated with atherosclerosis in type 2 diabetes patients with increased plasma adiponectin levels: a cross-sectional study.

BACKGROUND: Omentin and adiponectin are among the anti-inflammatory and anti-atherogenic adipokines that have potentially beneficial effects on cardiovascular disorders. Recent studies indicate a paradoxical relationship between adiponectin and cardiovascular mortality across many clinical settings including type 2 diabetes. In this study, we characterized the clinical features of type 2 diabetes patients with increased adiponectin levels and examined the association between omentin and atherosclerosis in those patients. METHODS: The subjects were 413 patients with type 2 diabetes. Fasting plasma omentin and total adiponectin levels were measured by enzyme-linked immunosorbent assay. The intima-media thickness (IMT) of the common carotid artery was measured by ultrasonography. The subjects were stratified according to the median value of plasma adiponectin. RESULTS: In high-adiponectin group, omentin levels were higher, while IMT tended to be greater than those in low-adiponectin group. The high-adiponectin group also exhibited older age, higher systolic blood pressure, lower kidney function, body mass index, and insulin resistance index compared to the low-adiponectin group. Multivariate analysis revealed that omentin levels were independently and negatively associated with IMT in high-adiponectin group, but not in low-adiponectin group, after adjusting for adiponectin levels and traditional cardiovascular risk factors. On the other hand, adiponectin levels were not significantly associated with IMT in either group. CONCLUSIONS: Plasma omentin levels are inversely associated with IMT in type 2 diabetes patients with increased adiponectin levels and multiple cardiovascular risk factors. This study suggests a protective role of omentin against atherosclerosis in type 2 diabetes patients, which is potentially influenced by adiponectin level and cardiovascular risk status.

Association of cystatin C- and creatinine-based eGFR with osteoporotic fracture in Japanese postmenopausal women with osteoporosis: sarcopenia as risk for fracture.

Coexistence of chronic kidney disease (CKD) is regarded as a risk for osteoporotic fracture particularly in postmenopausal women, not only because of increased parathyroid hormone level but also uremic sarcopenia. We examined the relationships of cystatin C-based glomerular filtration rate (eGFRcys) and creatinine-based GFR (eGFRcr), as well as their ratio with occurrence of osteoporotic fracture in postmenopausal osteoporotic women. This cross-sectional study included 555 postmenopausal women with osteoporosis. eGFRcr and eGFRcys were simultaneously measured, while occurrence of osteoporotic fracture was obtained by a medical chart review. Patients with osteoporotic fractures (n = 211) exhibited significantly lower levels of physical activity, eGFRcr, eGFRcys, and eGFRcys/eGFRcr ratios, while a higher percentage was CKD stage 3 or more, estimated by eGFRcr or eGFRcys (CKDcys), than those without (n = 344). Lower eGFRcys, but not lower eGFRcr, was independently associated with osteoporotic fracture in the entire cohort and that association was retained in CKDcys patients. Of great interest, higher eGFRcr was associated with osteoporotic fracture independent of eGFRcys in CKDcys patients. Furthermore, lower eGFRcys/eGFRcr ratio was independently associated with osteoporotic fracture in both CKDcys patients and the entire cohort. eGFRcys reduction might be associated with osteoporotic fracture in postmenopausal osteoporotic women, indicating the involvement of renal osteopathy in its occurrence. Furthermore, the association of higher, but not lower, eGFRcr with osteoporotic fracture in CKDcys cases might be explained by underestimation of renal dysfunction by eGFRcr resulting from decreased muscle mass and quality in those patients.

Thyroid blood flow in inferior thyroid artery as predictor for increase in levothyroxine dosage during pregnancy in women with Hashimoto's thyroiditis - a retrospective study.

BACKGROUND: We examined whether inferior thyroid artery peak systolic velocity (ITA-PSV) predicts an increase in levothyroxine (LT4) dosage in pregnant women with Hashimoto's thyroiditis. METHODS: Twenty-two women with Hashimoto's thyroiditis who were planning and later achieved pregnancy or confirmed as pregnant were enrolled in this retrospective longitudinal observational study. ITA-PSV and thyroid volume were measured using ultrasonography. Serum concentrations of free thyroxine (F-T4), free triiodothyronine (F-T3), and thyroid stimulating hormone (TSH) were simultaneously determined. We adjusted LT4 dosage to maintain serum TSH at < 2.5 µIU/mL (1st trimester) and later at < 3 µIU/mL (2nd, 3rd trimester). RESULTS: Eighteen patients (81.8%) required an increase in LT4 dosage during pregnancy, of whom 7 (31.8%) required an increase ≥50 µg. Multivariable regression analysis showed that TSH (ß = 0.507, p = 0.008) and ITA-PSV (ß = - 0.362, p = 0.047), but not thyroid volume, F-T4, or F-T3, were independently associated with increased LT4 dosage. Receiver-operating characteristic analysis for predicting an increase in LT4 ≥ 50 µg/day showed that the area under the curve (0.905) for ITA-PSV with TSH was not significantly increased (p = 0.123) as compared to that (0.743) for TSH alone, whereas integrated discrimination improvement was significantly increased (27.9%, p = 0.009). CONCLUSIONS: In pregnant patients with Hashimoto's thyroiditis, ITA-PSV was a significant predictor of increase in LT4 dosage independent of TSH level, while ITA-PSV plus TSH showed significantly improved predictability as compared to TSH alone. These results suggest that ITA-PSV reflects residual thyroid function and is useful for evaluating the need for increased thyroid hormone production in pregnant patients with Hashimoto's thyroiditis.