Patient-reported difficulty in activities of daily living and corresponding muscle weakness in elderly patients undergoing haemodialysis.

AIM: Patients undergoing haemodialysis have reduced muscle strength and impaired activities of daily living (ADL). We examined possible relationship between difficult ADL and corresponding muscle weakness in elderly haemodialysis patients. METHODS: This was a single-centre, cross-sectional study. Patient-reported ADL difficulty was examined using a questionnaire in six ADL using upper limbs (eating, grooming and dressing) and lower limbs (bathing, toileting and locomotion). We measured six muscle strengths by dynamometers of shoulder flexion, shoulder abduction, elbow flexion, handgrip, hip abduction and knee extension. The muscle strength with the lowest Z-score was considered as the weakest muscle strength for the patient. RESULTS: The six scores of ADL difficulty were all inversely associated with the six muscle strengths in the 81 total participants of whom 71 individuals (87.7%) had any ADL difficulty. Among the six measurements of muscle strength, handgrip strength showed the highest associations with all ADL difficulties. In 25 patients who perceived that the most difficult ADL was an activity using upper limbs, the common weakest muscle strengths were the hip abduction, handgrip and elbow flexion. In 44 patients who perceived that the most difficult ADL was an activity using lower limbs, knee extension was the most prevalent weakest muscle strength. CONCLUSION: This study suggested preferential relationship between the most difficult ADL and corresponding muscle weakness in elderly haemodialysis patients. This finding may be useful in prevention and treatment.

Serum phosphate as an independent factor associated with cholesterol metabolism in patients undergoing hemodialysis: a cross-sectional analysis of the DREAM cohort.

BACKGROUND: Hyperphosphatemia is a risk factor for cardiovascular outcomes in patients with chronic kidney disease. In an experimental model, hyperphosphatemia promoted atherosclerosis by activating sterol regulatory element-binding protein 2, which controls cholesterol homeostasis. In the present study, we hypothesized that serum phosphate level is associated with cholesterol metabolism in patients with kidney failure. METHODS: We conducted a single-center cross-sectional study including 492 patients undergoing hemodialysis and 100 healthy controls not on statin or ezetimibe treatment. Serum lathosterol and campesterol levels were measured as a marker of cholesterol synthesis and absorption, respectively. As compared with the control group, the hemodialysis patients had higher median phosphate {5.8 mg/dL [interquartile range (IQR 5.0-6.6) versus 3.3 (3.0-3.6); P < .001], lower lathosterol [1.2 µg/mL (IQR 0.8-1.7) versus 2.6 (1.9-3.4); P < .001] and higher campesterol levels [4.5 µg/mL (IQR 3.6-6.0) versus 4.1 (3.2-5.4); P = .02]. Serum phosphate correlated positively to campesterol in the control group (Spearman's r = 0.21, P = .03) and in hemodialysis patients (Spearman's r = 0.19, P < .001). The positive association between phosphate and campesterol levels in the hemodialysis group remained significant in multivariable-adjusted linear regression analysis. There was no significant association between phosphate and lathosterol in either group. CONCLUSIONS: An independent association was found between phosphate and campesterol levels in patients with kidney failure. This study suggests a novel relationship between phosphate and cholesterol metabolism, both of which could affect cardiovascular outcomes in this population.

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.

Clinical and histopathological features related to time to complete remission in adult-onset minimal change nephrotic syndrome patients with corticosteroid treatment.

BACKGROUND: Minimal change nephrotic syndrome (MCNS) is a common type of nephrotic syndrome in adults, though evidence regarding its clinical and histopathological features related to time to complete remission (CR) is limited. METHODS: This was a retrospective study of biopsy-proven, first-onset, adult MCNS patients who achieved CR after undergoing corticosteroid treatment. Body weight (BW) change rate was calculated as follows: (BW at admission - BW at discharge)/BW at discharge × 100. Histopathological examinations were performed, with particular attention given to tubulointerstitial lesions. RESULTS: Fifty-seven patients (median 41 years old, range 22-63 years; 37 males) were diagnosed with MCNS from 2007 to 2020. Time to CR was a median 11 (8-21) days. In addition to serum creatinine and urinary protein, BW change rate also showed a positive correlation with time to CR (rs = 0.438, p < 0.001; rs = 0.280, p = 0.035; rs = 0.544, p < 0.001; respectively), while multivariate Cox proportional hazards models also revealed those factors as significant predictors for longer time to CR. In MCNS patients with a higher BW change rate (n = 28), serum creatinine, urinary protein, histopathological score, and time to CR were significantly greater as compared to those with a lower BW change rate (n =29). Also, in those patients, histopathological interstitial edema was significantly associated with longer time to CR after adjustments for serum creatinine and urinary protein. CONCLUSION: The present results indicate that BW change rate can predict time to CR in adult-onset MCNS patients. Histopathologically, interstitial edema is also an important factor for time to CR in MCNS patients with greater BW increase.

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.

Nutritional Disorder Evaluated by the Geriatric Nutritional Risk Index Predicts Death After Hospitalization for Infection in Patients Undergoing Maintenance Hemodialysis.

OBJECTIVE: Infection is related to a higher rate of hospitalization and subsequent death in patients undergoing hemodialysis. Limited data are available about factors associated with death after hospitalization for infection. Nutritional disorder also known as protein energy wasting is profoundly associated with poor consequences. The Geriatric Nutritional Risk Index (GNRI) is a simple but useful nutritional screening tool to predict mortality. We examined whether the GNRI could predict hospitalization for infection and subsequent death. DESIGN AND METHODS: This was a prospective cohort study on patients undergoing hemodialysis. The predictor was the GNRI. The patients were divided into tertiles of the GNRI (T1 to T3), with the highest tertile of T3 as the referent. The outcomes of interest were all-cause mortality, hospitalization for infection, and subsequent death. RESULTS: Of 518 patients, 107 patients died (median follow-up period: 5.0 years; interquartile range: 3.6-5.0) and 169 patients experienced new hospitalization for infection (median follow-up period: 4.5 years; interquartile range: 3.4-5.0) during the follow-up period from December 2004 to December 2009. A lower GNRI was a significant predictor for all-cause mortality in multivariable Cox models (hazard ratio [HR]: 2.9, 95% confidential interval [CI]: 1.5-5.5, P < .001 for T1 vs. T3). However, the GNRI was not associated with hospitalization for infection in multivariable Fine-Gray models with death as a competing risk (subdistributional HR: 1.5, 95% CI: 1.0-2.3, P = .056 for T1 vs. T3). After hospitalization for infection, 38 patients died during the subsequent 2.5-year follow-up period. The GNRI was a significant predictor of death after hospitalization for infection in multivariable Cox models (HR: 2.7, 95% CI: 1.3-5.6, P = .006 for T1 vs. T2+T3). CONCLUSIONS: A lower GNRI predicted a higher risk of all-cause mortality but not hospitalization for infection. However, a lower GNRI was significantly associated with a higher risk of mortality after hospitalization for infection. These findings suggest that long-term mortality after hospitalization for infection was predicted by nutritional disorder evaluated by the GNRI.

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.

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.

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.

Suppression of thyrotropin secretion during roxadustat treatment for renal anemia in a patient undergoing hemodialysis.

BACKGROUND: Inhibition of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) is a novel choice for the treatment of renal anemia, and an oral HIF-PH inhibitor roxadustat was approved for renal anemia. Roxadustat has high affinity to thyroid hormone receptor beta, which may affect thyroid hormone homeostasis. CASE PRESENTATION: We present here a patient undergoing hemodialysis with primary hypothyroidism receiving levothyroxine replacement, who showed decreased free thyroxine (FT4) and thyroid stimulating hormone (TSH) after starting roxadustat. Pituitary stimulation test revealed selective suppression of TSH secretion. Recovery of TSH and FT4 levels after stopping roxadustat suggested the suppression of TSH was reversible. CONCLUSIONS: Physicians should pay special attention to thyroid hormone abnormalities in treatment with roxadustat.

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.

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.

Increased Glomerular Hydrostatic Pressure is Associated with Tubular Creatinine Reabsorption in Healthy Subjects.

BACKGROUND: Cr is secreted by the proximal tubules and thus Cr clearance (Ccr) can overestimate inulin clearance (Cin). However, in some cases, Ccr can even underestimate Cin. This suggests that Cr could be reabsorbed in the tubuli. We examined the clinical parameters that are associated with tubular Cr reabsorption. METHODS: In 80 kidney donor candidates (53.9 ± 13.2 years, 29 males), Cin and para-aminohippuric acid clearance were measured simultaneously. Intrarenal hemodynamic parameters were calculated by Gomez's formulae. To quantify the secretory component of Ccr (SFcr), it was calculated as follows: SFcr = (Ccr - Cin)/Ccr. RESULTS: Twenty-five subjects (31.3%) showed SFcr values <0. SFcr that correlated significantly and negatively with efferent arteriolar resistance (Re) and glomerular hydrostatic pressure (Pglo) (Re: r = -0.30, p = 0.008; Pglo: r = -0.28, p = 0.025). In multiple regression analyses, Re and Pglo were significantly and negatively associated with SFcr after adjustment for other confounders. CONCLUSIONS: These findings suggest that tubular reabsorption of Cr can occur in some cases. Intrarenal glomerular hemodynamic burden may be related to tubular creatinine reabsorption, which possibly leads to lower Ccr values.

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.

Impact of diabetes on sarcopenia and mortality in patients undergoing hemodialysis.

BACKGROUND: Sarcopenia has become a serious disorder in modern society. Chronic kidney disease requiring dialysis and diabetes are some of the disorders that accelerate the onset and progression of sarcopenia. We, therefore, investigated the prevalence of sarcopenia in patients undergoing hemodialysis (HD) and confirmed the impact of diabetes mellitus (DM) on this population. METHODS: This study included 308 patients whose muscle strength and mass had been evaluated using handgrip strength and dual-energy X-ray absorptiometry, respectively. Sarcopenia was defined according to the criteria established by the Asian Working Group on Sarcopenia. In addition, this cohort had been followed up for 9 years. RESULTS: The prevalence of sarcopenia was 40% (37% in males and 45% in females) with gender differences being insignificant (p = 0.237). The DM morbidity rate was significantly higher in those with sarcopenia than in those without sarcopenia (41% vs. 27%, p = 0.015). Multivariate regression analyses showed that the presence of DM was an independent contributor to sarcopenia in patients undergoing HD (odds ratio 3.11; 95% confidence interval 1.63-5.93; p <  0.001). During the follow-up of 76 ± 35 months, 100 patients died. Patients with sarcopenia demonstrated significantly higher rates of all-cause mortality than those without sarcopenia (p <  0.001 using the log-rank test). Multivariate Cox proportional hazards analyses revealed that the presence of DM was significantly associated with higher all-cause mortality (adjusted hazard ratio: 2.39; 95% confidence interval 1.51-3.81; p <  0.001). CONCLUSIONS: The prevalence of sarcopenia among this cohort of patients undergoing HD was determined to be 40%. Moreover, the presence of DM was an independent contributor to sarcopenia and an independent predictor of all-cause mortality in this population.

Inverse association of fat mass, but not lean mass, with glycated albumin in hemodialysis patients with or without diabetes mellitus.

Background: Glycated albumin (GA), which is independent of anemia and/or use of erythropoiesis-stimulating agents, might provide a more precise measure than glycated hemoglobin (HbA1c) in hemodialysis patients. The present study examines whether body composition is associated with GA besides glycemic control in hemodialysis patients. Methods: This study included 90 hemodialysis patients with diabetes mellitus (DM) and 86 hemodialysis patients without DM. We examined blood parameters after an overnight fast and body fat and lean mass using dual X-ray absorptiometry 21-24 h after completing the dialysis session. Results: The mean body mass index (BMI) was 22.0 kg/m2. BMI and truncal fat mass were significantly higher, and total fat mass tended to be higher in hemodialysis patients with DM than in those without DM. GA exhibited inverse correlations with BMI, total lean mass, total fat mass, and truncal fat mass in hemodialysis patients with and without DM; however, there was a lack of correlation with total lean mass in patients without DM. In multiple regression analysis including total fat mass and total lean mass simultaneously as independent variables, total fat mass (with DM: ß = -0.322, p = .006) (without DM: ß = -0.391, p < .001), but not total lean mass, in addition to log fasting plasma glucose, emerged as an independent factor associated with GA in hemodialysis patients with and without DM. When total fat mass was replaced with truncal fat mass (with DM: ß = -0.311, p = .007) (without DM: ß = -0.396, p < .001), the association remained significant and independent with GA in both patient groups. Conclusions: Higher total fat mass, particularly truncal fat mass, might be associated with lower GA levels, beside glycemic control, in hemodialysis patients with or without DM.

Urinary Iron Excretion is Associated with Urinary Full-Length Megalin and Renal Oxidative Stress in Chronic Kidney Disease.

BACKGROUND/AIMS: Megalin mediates the uptake of glomerular-filtered iron in the proximal tubules. Urinary full length megalin (C-megalin) excretion has been found to be increased in association with megalin-mediated metabolic load to the endo-lysosomal system in proximal tubular epithelial cells (PTECs) of residual nephrons. In the present study, we investigated the association between urinary iron and C-megalin in chronic kidney disease (CKD) patients, and the possible harmful effect of iron in renal tubules. METHODS: Urinary levels of iron and C-megalin were measured in 63 CKD patients using automatic absorption spectrometry and a recently-established sandwich ELISA, respectively. RESULTS: Although both urinary C-megalin and urinary total protein levels were correlated with urinary iron (C-megalin: ρ = 0.574, p <0.001; total protein: ρ = 0.500, p <0.001, respectively), urinary C-megalin alone emerged as an independent factor positively associated with urinary iron (ß = 0.520, p <0.001) (R2 = 0.75, p <0.001). Furthermore, urinary iron was significantly and positively associated with urinary 8-hydroxydeoxyguanosine, an oxidative stress marker, while no association with other markers of renal tubular injury, i.e., ß2-microglobulin and N-acetyl-ß-D-glucosaminidase, was noted. CONCLUSIONS: Our findings suggest that renal iron handling may be associated with megalin-mediated endo-lysosomal metabolic load in PTECs of residual nephrons and oxidative stress in renal tubules.