Gentle, Massage-like, Head Stroking Provokes Salivary Oxytocin Release.

Context: The evidence is growing that oxytocin (OXT), a hypothalamic hormone, can induce parturition and lactation, modulate affiliative behavior, and regulate stress and energy metabolism. Although the physiological effects of massage aren't fully understood, massage may affect OXT release and facilitate adaptive responses to stressors. Objectives: This study intended to examine the effects of gentle, massage-like head, stroking to determine whether it could have a direct influence on the release of OXT. Design: The research team performed a preliminary study. Setting: The study was conducted at Kanazawa Medical University in Kahoku and Mizuho Hospital, Tsubata, Ishikawa, Japan. Participants: Participants were 14 volunteers from Mizuho Hospital. Intervention: The 14 recruited participants were assigned to the massage group and received gentle, massage-like, head stroking, which lasted 60 minutes. Seven of those participants were randomly recruited to become a control group that rested only, without massage, on a different day than the massage occurred. Outcome Measures: Participants' saliva for both groups was drawn at baseline and postintervention on the different days. Salivary OXT was assayed using a highly sensitive chemiluminescence immunoassay. Analyses were performed at baseline before the intervention and postintervention. Results: The OXT secretion increased significantly in the massage group unlike in the rest group, which had no change. Conclusions: Gentle, massage-like, head stroking is an effective method of releasing endogenous OXT. These findings open up the possibility of using endogenous OXT as an adjunct therapy in both clinical and research settings.

Oral Iron Absorption of Ferric Citrate Hydrate and Hepcidin-25 in Hemodialysis Patients: A Prospective, Multicenter, Observational Riona-Oral Iron Absorption Trial.

Oral ferric citrate hydrate (FCH) is effective for iron deficiencies in hemodialysis patients; however, how iron balance in the body affects iron absorption in the intestinal tract remains unclear. This prospective observational study (Riona-Oral Iron Absorption Trial, R-OIAT, UMIN 000031406) was conducted at 42 hemodialysis centers in Japan, wherein 268 hemodialysis patients without inflammation were enrolled and treated with a fixed amount of FCH for 6 months. We assessed the predictive value of hepcidin-25 for iron absorption and iron shift between ferritin (FTN) and red blood cells (RBCs) following FCH therapy. Serum iron changes at 2 h (ΔFe2h) after FCH ingestion were evaluated as iron absorption. The primary outcome was the quantitative delineation of iron variables with respect to ΔFe2h, and the secondary outcome was the description of the predictors of the body's iron balance. Generalized estimating equations (GEEs) were used to identify the determinants of iron absorption during each phase of FCH treatment. ΔFe2h increased when hepcidin-25 and TSAT decreased (-0.459, -0.643 to -0.276, p = 0.000; -0.648, -1.099 to -0.197, p = 0.005, respectively) in GEEs. FTN increased when RBCs decreased (-1.392, -1.749 to -1.035, p = 0.000) and hepcidin-25 increased (0.297, 0.239 to 0.355, p = 0.000). Limiting erythropoiesis to maintain hemoglobin levels induces RBC reduction in hemodialysis patients, resulting in increased hepcidin-25 and FTN levels. Hepcidin-25 production may prompt an iron shift from RBC iron to FTN iron, inhibiting iron absorption even with continued FCH intake.

Effects of an additional resistance training intervention in hemodialysis patients performing long-term ergometer exercise during dialysis.

[Purpose] To verify the effect of a 12-week additional resistance training intervention in patients on hemodialysis who had been performing supine ergometer exercises alone during dialysis. [Participants and Methods] Overall, 18 patients undergoing hemodialysis were included. A 12-week intervention with additional resistance training was conducted in hemodialysis patients who had been performing supine ergometer exercise for 30 min during dialysis for over >3 months. Physical function before and after the period of bicycle ergometer exercise alone and before and during the additional intervention was compared. Resistance training consisted of 1-3 sets per day of five different exercises for the large muscle groups of the upper and lower limbs. [Results] The results of the 6-min walk test improved significantly after the additional intervention. The average driving distance in the supine ergometer exercise during the additional intervention was identified as an associated factor. [Conclusion] The addition of the resistance training to long-term supine ergometer exercisers improved walking endurance. When supine ergometer exercise alone does not change physical function, the additional use of resistance training subsequently may have a positive effect on walking endurance.

Relationship between anti-erythropoietin receptor autoantibodies and responsiveness to erythropoiesis-stimulating agents in patients on hemodialysis: a multi-center cross-sectional study.

BACKGROUND: A decreased response to erythropoiesis-stimulating agents (ESAs) leads to refractory anemia and worse prognosis in patients with chronic kidney disease. We examined the association between autoantibodies to the erythropoietin receptor (EPOR) and responsiveness to ESAs in patients on maintenance hemodialysis. METHODS: A total of 108 Japanese patients on maintenance hemodialysis at three institutions were enrolled. Sera from these patients were screened for anti-EPOR antibodies using an enzyme-linked immunosorbent assay. An ESA resistance index (ERI) was calculated, and patients in the highest ERI quartile were defined as ESA hyporesponsive. RESULTS: Anti-EPOR antibodies were detected in 11 patients (10%). Body mass index and hemoglobin, platelet, magnesium, and ferritin levels decreased with higher ERI levels. On the other hand, C-reactive protein (CRP) levels and the prevalence of anti-EPOR antibodies increased with higher ERI levels. In multivariate analysis, the presence of anti-EPOR antibodies together with CRP was a significant risk factor for ESA hyporesponsiveness. CONCLUSIONS: Anti-EPOR antibodies were detected in patients on maintenance hemodialysis, and these autoantibodies were independent factors for hyporesponsiveness to ESAs in these patients.

Decline in estimated glomerular filtration rate is associated with risk of end-stage renal disease in type 2 diabetes with macroalbuminuria: an observational study from JDNCS.

BACKGROUND: There is increased interest in surrogate endpoints for clinical trials of chronic kidney disease. METHODS: In this nationwide observational study of 456 patients with type 2 diabetes and clinically suspected diabetic nephropathy followed for a median of 4.2 years, we evaluated the association between estimated glomerular filtration rate (eGFR) and albuminuria at baseline or during follow-up and risk of ESRD. RESULTS: Low eGFR (<60 mL/min/1.73 m2) and macroalbuminuria at enrollment were independently associated with risk of ESRD. In patients with macroalbuminuria, both ≤-50% change and -50 to -30% change in eGFR over 1 and 2 years were predictive of ESRD. The higher cut point (≥50% decline in eGFR) was more strongly predictive but less common. Remission of macroalbuminuria to normo-/microalbuminuria at 1 and 2 years was associated with a lower incidence of ESRD than no remission; however, it was not a determinant for ESRD independently of initial eGFR and initial protein-to-creatinine ratio. CONCLUSION: These results suggest that a ≥30% decline in eGFR over 1 or 2 years adds prognostic information about risk for ESRD in patients with type 2 diabetes and macroalbuminuria, supporting the consideration of percentage decline in eGFR as a surrogate endpoint among macroalbuminuric cases in type 2 diabetes. On the other hand, our study suggests that additional analyses on the relationship between remission of macroalbuminuria and risk of ESRD are needed in type 2 diabetes.

Validity of body impedance analysis for evaluating body composition in patients undergoing long-term hemodialysis.

[Purpose] This study assessed changes in body composition before and after dialysis in chronic hemodialysis patients and determined the relationships between various body composition parameters and blood lipid levels in these patients. [Subjects] The cross-sectional study included 19 dialysis outpatients (17 men and 2 women, aged 35-82 years). [Methods] Body mass index, body weight, percent body fat, and percent skeletal muscle were measured before and after dialysis by using body impedance analysis. Blood lipid levels were obtained from patients' clinical records. The body composition parameters before and after dialysis were compared using paired t-tests. Spearman's rank correlation coefficients were calculated to determine relationships between the body composition parameters, before and after dialysis, and the blood lipid levels. [Results] All body composition parameters differed significantly before and after dialysis. High-density lipoprotein cholesterol level significantly correlated with all the body composition parameters, whereas total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels significantly correlated with some of these parameters. The correlation coefficients revealed no major differences in the relationships between blood lipid parameters and body compositions before and after dialysis. [Conclusion] Our findings suggest that body composition parameters, whether measured before or after dialysis, can be used to evaluate obesity in longitudinal studies.

Japan Diabetic Nephropathy Cohort Study: study design, methods, and implementation.

BACKGROUND: Diabetic nephropathy, leading to end-stage renal disease, has a considerable impact on public health and the social economy. However, there are few national registries of diabetic nephropathy in Japan. The aims of this prospective cohort study are to obtain clinical data and urine samples for revising the clinical staging of diabetic nephropathy, and developing new diagnostic markers for early diabetic nephropathy. METHODS: The Japanese Society of Nephrology established a nationwide, web-based, and prospective registry system. On the system, there are two basic registries; the Japan Renal Biopsy Registry (JRBR), and the Japan Kidney Disease Registry (JKDR). In addition to the two basic registries, we established a new prospective registry to the system; the Japan Diabetic Nephropathy Cohort Study (JDNCS), which collected physical and laboratory data. RESULTS: We analyzed the data of 321 participants (106 female, 215 male; average age 65 years) in the JDNCS. Systolic and diastolic blood pressure was 130.1 and 72.3 mmHg, respectively. Median estimated glomerular filtration rate (eGFR) was 33.3 ml/min/1.73 m(2). Proteinuria was 1.8 g/gCr, and serum levels of albumin were 3.6 g/dl. The majority of the JDNCS patients presented with preserved eGFR and low albuminuria or low eGFR and advanced proteinuria. In the JRBR and JKDR registries, 484 and 125 participants, respectively, were enrolled as having diabetes mellitus. In comparison with the JRBR and JKDR registries, the JDNCS was characterized by diabetic patients presenting with low proteinuria with moderately preserved eGFR. CONCLUSIONS: There are few national registries of diabetic nephropathy to evaluate prognosis in Japan. Future analysis of the JDNCS will provide clinical insights into the epidemiology and renal and cardiovascular outcomes of type 2 diabetic patients in Japan.

Intra-Brain and Plasma Levels of L-Serine Are Associated with Cognitive Status in Patients with Chronic Kidney Disease.

Introduction: The number of patients with chronic kidney disease (CKD) is increasing worldwide. Cognitive impairment is one of the comorbidities of CKD. With the increased number of aged population, novel biomarkers of impaired cognitive function are required. Intra-body profile of amino acid (AA) is reportedly altered in patients with CKD. Although some AAs act as neurotransmitters in the brain, it is not clear whether altered AA profile are associated with cognitive function in patients with CKD. Therefore, intra-brain and plasma levels of AAs are evaluated with respect to cognitive function in patients with CKD. Methods: Plasma levels of AAs were compared between 14 patients with CKD, including 8 patients with diabetic kidney disease, and 12 healthy controls to identify the alteration of specific AAs in CKD. Then, these AAs were evaluated in the brains of 42 patients with brain tumor using non-tumor lesion of the resected brain. Cognitive function is analyzed with respect to intra-brain levels of AAs and kidney function. Moreover, plasma AAs were analyzed in 32 hemodialyzed patients with/without dementia. Results: In patients with CKD, plasma levels of asparagine (Asn), serine (Ser), alanine (Ala), and proline (Pro) were increased as compared to patients without CKD. Among these AAs, L-Ser, L-Ala, and D-Ser show higher levels than the other AAs in the brain. Intra-brain levels of L-Ser was correlated with cognitive function and kidney function. The number of D-amino acid oxidase or serine racemase-positive cells was not correlated with kidney function. Moreover, the plasma levels of L-Ser are also decreased in patients with declined cognitive function who are treated with chronic hemodialysis. Conclusion: The decreased levels of L-Ser are associated with impaired cognitive function in CKD patients. Especially, plasma L-Ser levels may have a potential for novel biomarker of impaired cognitive function in patients with hemodialysis.

Effect of Intradialytic Supine Ergometer Exercise on Hemodialysis Patients with Different Nutritional Status.

OBJECTIVE: It is important for hemodialysis patients to exercise while their nutritional status is being monitored. This study aimed to examine the difference in physical exercise function and the effect of exercise intervention in hemodialysis patients who were divided into two groups (high-nutrition and low-nutrition groups) based on the serum albumin levels. METHOD: A total of 26 outpatients (18 men and 8 women) undergoing hemodialysis (age: 66 ± 10 years) were included in this study. The patients' body composition data (weight, body mass index, percentage of body fat, fat-free mass, and total body water) and physical functions (grip strength, knee extensor strength, open-eyed one-legged standing time, long sitting trunk anteflexion, and 6-minute walking distance [6MWD] test) were measured. The intervention was supine ergometer exercise during hemodialysis, and the patients exercised for 30 minutes during hemodialysis thrice a week. The intervention period was three months. RESULTS: Compared to the high-nutrition group, the low-nutrition group showed a significant decrease in muscle strength. Furthermore, long sitting trunk anteflexion in the high-nutrition group and 6MWD in the low-nutrition group improved significantly after the intervention. CONCLUSION: The result of this study may indicate that 6MD can be improved by exercise during dialysis, regardless of nutritional status. It is said that low nutritional status has a negative impact on survival rate; thus, considering the impact on survival rate, it is hemodialysis patients with a low nutritional status that should be considered to introduce more active exercise during dialysis.

Increased levels of oral Streptococcus-derived D-alanine in patients with chronic kidney disease and diabetes mellitus.

The number of patients on hemodialysis is increasing globally; diabetes mellitus (DM) complications is the major cause of hemodialysis in patients with chronic kidney disease (CKD). The D-amino acid (AA) profile is altered in patients with CKD; however, it has not been studied in patients with CKD and DM. Furthermore, bacteria responsible for altering the D-AA profile are not well understood. Therefore, we examined the D-AA profiles and associated bacteria in patients with CKD, with and without DM. We enrolled 12 healthy controls and 54 patients with CKD, with and without DM, and determined their salivary, stool, plasma, and urine chiral AA levels using two-dimensional high-performance liquid chromatography. We performed 16S rRNA gene sequencing analysis of the oral and gut microbiota to determine the association between the abundance of bacterial species and D-AA levels. Plasma D-alanine and D-serine levels were higher in patients with CKD than in healthy adults (p < 0.01), and plasma D-alanine levels were higher in patients with CKD and DM than in those without DM. The abundance of salivary Streptococcus, which produced D-alanine, increased in patients with CKD and DM and was positively correlated with plasma D-alanine levels. Patients with CKD and DM had unique oral microbiota and D-alanine profiles. Plasma D-alanine is a potential biomarker for patients with CKD and DM.

Association between Anti-Erythropoietin Receptor Antibodies and Cardiac Function in Patients on Hemodialysis: A Multicenter Cross-Sectional Study.

Cardiac dysfunction is an important prognostic predictor of cardiovascular mortality in patients on hemodialysis (HD). Erythropoietin (EPO) has been reported to improve cardiac function by binding to the EPO receptor (EPOR) on cardiomyocytes. This study investigated whether anti-EPOR antibodies were associated with left ventricular cardiac function in patients undergoing HD. This multicenter, cross-sectional observational study included 377 patients (median age, 70 years; 267 (70.8%) males) with chronic kidney disease (CKD) undergoing stable maintenance HD. Serum levels of anti-EPOR antibodies were measured, and echocardiography was used to assess the left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF). Anti-EPOR antibodies were found in 17 patients (4.5%). LVMI was greater (median of 135 g/m2 vs. 115 g/m2, p = 0.042), and the prevalence of LVEF < 50% was higher (35.3% vs. 15.6%, p = 0.032) in patients with anti-EPOR antibodies than in those without. Multivariable linear regression and logistic regression analysis (after adjusting for known risk factors of heart failure) revealed that anti-EPOR antibodies were independently associated with LVMI (coefficient 16.2%; 95% confidence interval (CI) 1.0−35.0%, p = 0.043) and LVEF <50% (odds ratio 3.20; 95% CI 1.05−9.73, p = 0.041). Thus, anti-EPOR antibody positivity was associated with left ventricular dysfunction in patients undergoing HD.

Propagermanium administration for patients with type 2 diabetes and nephropathy: A randomized pilot trial.

AIMS: We assessed the potential efficacy and safety of propagermanium (PG), an organic compound that inhibits the C-C chemokine receptor type 2, administration in patients with type 2 diabetes and nephropathy. Furthermore, we assessed the feasibility of future studies. MATERIALS AND METHODS: We recruited patients from nine medical institutions in Japan for this randomized, open-label, parallel two-arm pilot trial. Inclusion criteria were diagnosis of type 2 diabetes, age 30-75 years, dipstick proteinuria of ≥1+ or urinary albumin-to-creatinine ratio (UACR) of ≥30 mg/g and estimated glomerular filtration rate of ≥30 mL/min/1.73 m2. Patients were randomly assigned (1:2) using a minimization algorithm to either continuing usual care or concomitant administration of 30 mg PG per day for 12 months. The primary outcome was the change in UACR from baseline to 12 months. We also collected safety information for all patients who received at least one dose of PG. RESULTS: We enrolled 29 patients, 10 were assigned to continue usual care and 19 to receive PG. Changes in UACR by PG in addition to the usual care were 25.0% (95% CI -20.4%, 96.5%, P = .33). No severe adverse events or renal events were observed during the study. CONCLUSION: Although the treatment with PG was generally well tolerated, the dosage of 30 mg/d for 12 months did not reduce albuminuria when used in addition to usual care in patients with type 2 diabetes and nephropathy. Efficacy of PG should be verified in future definitive trials.

Effect of sevelamer hydrochloride on markers of bone turnover in Japanese dialysis patients with low biointact PTH levels.

BACKGROUND: In hemodialysis patients, adynamic bone disease has been reported to be closely associated with low levels of parathyroid hormone (PTH) due to exposure to high levels of serum calcium following the administration of calcium carbonate (CaCO3) or vitamin D agents. This study was conducted to clarify the therapeutic effect of a non-calcemic phosphate binder, sevelamer hydrochloride (sevelamer), for hypoparathyroidism in hemodialysis patients with or without diabetes mellitus. METHODS: Based on entry criteria, 40 Japanese chronic hemodialysis patients (22 males and 18 females with a mean age of 60.6, 14 diabetic patients and 26 non-diabetic patients) were switched from CaCO3 to sevelamer for 48 weeks. Serum calcium, phosphate, intact (i) PTH and PTH-(1-84) were analyzed. Bone remodeling activity was evaluated by determining intact osteocalcine (iOC), bone-specific alkaline phosphatase (BAP). RESULTS: The switch from CaCO3 to sevelamer significantly decreased the serum levels of calcium, resulting in the elevation of iPTH levels from 31+/-18 pg/mL to 95+/-96 pg/mL by 48 weeks. In contrast, serum phosphate levels remained similar to those in patients with CaCO3 treatment. Concomitantly, the levels of BAP and iOC were elevated. Further, these beneficial effects on bone turnover were observed in both diabetic and non-diabetic patients. CONCLUSION: Sevelamer reduced the calcium concentration and thereby increased PTH levels, resulting in the improvement of markers of bone turnover. The administration of sevelamer is of therapeutic benefit for the improvement of bone remodeling activity even in hemodialysis patients with diabetes.