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Abstract Background Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) exert a renoprotective effect on patients with chronic kidney disease (CKD). Despite their benefit, one of their side effects is hyperkalemia, and it is one of the most common reasons for discontinuation of these drugs. Hyperchloremic metabolic acidosis is a known risk factor for hyperkalemia in patients with CKD. However, whether it is a risk factor for hyperkalemia after initiating ACE-I or ARB remains unclear. Methods In a previous study, serum sodium minus chloride level ([Na+) − (Cl−]) was identified as useful for diagnosing metabolic acidosis. To estimate the baseline acid–base status, we determined for the cutoff value of [Na+] − [Cl−] that correlates with [HCO3 −] below 24 mEq/L in patients with CKD. We then investigated whether this cutoff value was associated with hyperkalemia (serum potassium level ≥ 5.0 mEq/L) after initiating ACE-I or ARB in patients with CKD. Results In the investigation of the cutoff value of [Na+] − [Cl−], 612 patients were examined, and [Na+] − [Cl−] showed a good correlation with [HCO3 −] (r = 0.67, p

Abstract Fatigue in hemodialysis recipients interferes with daily activities and renal rehabilitation, and its underlying causes and treatment remain unclear. Psychological factors, like illness perceptions and alexithymia, cause fatigue in other diseases; however, their contribution to hemodialysis-related fatigue is unknown. This cross-sectional study included 53 hemodialysis recipients. To assess participants’ fatigue, we used a self-administered patient-reported outcome questionnaire whose items have shown correlation with those of established scales, such as the Profile of Mood States and Visual Analogue Scales. The associations among the scores of the revised Illness Perceptions Questionnaire (IPQ-R), Toronto Alexithymia Scale (TAS-20), and Hospital Anxiety and Depression Scale and fatigue were analyzed using bivariable and multivariable analyses. Patients with fatigue had significantly higher median scores for the IPQ-R subscales “Identity” and “Negative emotional representation about illness” than those without fatigue, suggesting the association of specific illness perception with fatigue. Median scores for the TAS-20 subscale “Difficulty identifying feelings” were also significantly higher among fatigued patients, suggesting the association of alexithymia with fatigue. Depression was not associated with fatigue. Multivariable logistic regression revealed the association of a high “Identity” score with the risk of fatigue (adjusted odds ratio, 1.32; 95% confidence interval, 1.00–1.73; P = 0.04), while there were no significant association between a high “Difficulty identifying feelings” score and the risk of fatigue (adjusted odds ratio, 1.09; 95% confidence interval, 0.95–1.24). Specific illness perception and alexithymia were slightly associated with hemodialysis-related fatigue. Cognitive-behavioral therapy for these conditions could reduce fatigue and promote renal rehabilitation.

Abstract Background In the Japanese guidelines on combination peritoneal dialysis (PD) and hemodialysis (HD) therapy, patients with serum beta 2 microglobulin (β2MG) levels less than 30 mg/L are recommended. And PD patients with β2MG more than 30 mg/L are considered to transfer to the PD + HD combination therapy. However, the resultant changes in serum β2MG levels by the introduction of PD + HD combination therapy and the factors influencing the change have not clearly elucidated. Methods We retrospectively studied 11 PD patients (mean age 56.4 ± 12.9 years, 10 males) with baseline β2MG levels > 30 mg/L with respect to changes in β2MG and its related factors for 12 months after the introduction of combination therapy of PD plus once a week HD (4 h) using a high-performance dialyzer. Laboratory data including hemoglobin, albumin, C-reactive protein, blood urea nitrogen, creatinine, and the patients’ demographic profiles, and HD-related factors, such as Kt/V and blood flow rate, were assessed. Results Serum β2MG levels decreased statistically significantly after the introduction of combination therapy: from 36.7 ± 6.7 mg/L at 0 months, to 33.4 ± 6.1 mg/L at 3 months (p = 0.030, compared to baseline), 32.9 ± 4.5 mg/L at 6 months (p = 0.009), and 33.3 ± 5.3 mg/L at 12 months (p = 0.023), respectively. However, only 27–36% patients achieved target β2MG levels of

Chronic kidney disease (CKD), which is globally on the rise, has become an urgent challenge from the perspective of public health, given its risk factors such as end-stage renal failure, cardiovascular diseases, and infections. The pathophysiology of CKD, including dialysis patients, is deeply associated with enhanced oxidative stress in both the kidneys and the entire body. Therefore, the introduction of a safe and widely applicable antioxidant therapy is expected as a measure against CKD. Electrolyzed hydrogen water (EHW) generated through the electrolysis of water has been confirmed to possess chemical antioxidant capabilities. In Japan, devices producing this water have become popular for household drinking water. In CKD model experiments conducted to date, drinking EHW has been shown to suppress the progression of kidney damage related to hypertension. Furthermore, clinical studies have reported that systemic oxidative stress in patients undergoing dialysis treatment using EHW is suppressed, leading to a reduction in the incidence of cardiovascular complications. In the future, considering EHW as one of the comprehensive measures against CKD holds significant importance. The medical utility of EHW is believed to be substantial, and further investigation is warranted.

Abstract Background Reportedly, dialysis solutions containing molecular hydrogen (H2) might ameliorate patient-reported fatigue in hemodialysis (HD) patients. However, it is unknown whether its impact might differ with different H2 levels. Method This single-arm, prospective observational study examined 105 patients on chronic HD (62 males; mean age, 66 years; mean HD duration, 117 months). All patients were originally treated with an HD solution with 47 ppb (mean) H2 for more than 12 months, followed by an HD solution with 154 ppb (mean) H2 for 8 weeks. Baseline and changes in subjective fatigue status rated on a numerical rating scale (NRS) were assessed before the start of the study (baseline) and 8th week of the study. Results Patients were classified into three groups according to the presence of subjective fatigue at baseline: Group A (15.2%), presence of fatigue on both HD and HD-free days; Group B (28.6%), fatigue only on HD days; and Group C (56.2%), freedom from fatigue. In Group A, NRS scores during the 8-week period were significantly decreased as compared with 0 week, at the 4th and 8th week on HD days, and at the 8th week on HD-free day, respectively. While no consistent changes were found in other groups. At the 8th week, 64 patients (61%) presented absence of or decrease in the NRS score of fatigue, while the rest of patients did not present the decrease in NRS (the non-improved: 39%). Regarding the factors related to the non-improved, prescription of antihypertensive agents was a significant independent risk factor by multivariate analysis, indicating the possible involvement of excess fall in blood pressure (BP) in those patients. Conclusion Amelioration of the patient-reported outcome of fatigue might be influenced by H2 levels in the HD solution, and the optimal H2 level in the dialysate needs to be elucidated in consideration of clinical type of fatigue and BP control status.

Dental caries are an oral infectious disease that can affect human health both orally and systemically. It remains an urgent issue to establish a novel antibacterial method to prevent oral infection for a healthy life expectancy. The aim of this study was to evaluate the inhibitory effects of novel iron chelators, super-polyphenols (SPs), on the cariogenic bacterium Streptococcus mutans, in vitro. SPs were developed to reduce the side effects of iron chelation therapy and were either water-soluble or insoluble depending on their isoforms. We found that SP6 and SP10 inhibited bacterial growth equivalent to povidone-iodine, and viability tests indicated that their effects were bacteriostatic. These results suggest that SP6 and SP10 have the potential to control oral bacterial infections such as Streptococcus mutans.

Abstract The ASTRIO study was a randomised, multicentre, 24-week study that compared the effects of ferric citrate hydrate (FC) and non-iron-based phosphate binders (control) on anaemia management in haemodialysis (HD) patients receiving erythropoiesis-stimulating agents (ESAs). In that study, FC reduced the doses of ESAs and intravenous iron without affecting haemoglobin (Hb); however, the cost-effectiveness of FC was unclear. We retrospectively implemented a cost-effectiveness analysis comparing the incremental cost-effectiveness ratios (ICERs) in FC (n = 42) and control (n = 40) groups in patients with serum phosphate and Hb controlled within the ranges of 3.5–6.0 mg/dL and 10–12 g/dL, respectively. Costs included drug costs of phosphate binders, ESAs, and intravenous iron. Elevated red cell distribution width (RDW) has been reported to be associated with mortality in HD patients and was therefore used as an effectiveness index. The mean (95% confidence interval) differences in drug costs and RDW between the FC and control groups were US$ − 421.36 (− 778.94 to − 63.78, p = 0.02) and − 0.83% (− 1.61 to – 0.05, p = 0.04), respectively. ICER indicated a decrease of US$ 507.66 per 1% decrease in RDW. FC was more cost-effective than non-iron-based phosphate binders. Iron absorbed via FC could promote erythropoiesis and contribute to renal anaemia treatment.

Abstract Background Fibroblast growth factor-23 (FGF23) and α-klotho are associated with anemia in patients with chronic kidney disease. In this post hoc analysis of the ASTRIO study (UMIN000019176), we investigated the relationship between FGF23 and α-klotho during treatment with an iron-based phosphate binder, ferric citrate hydrate (FC), compared with non-iron-based phosphate binders in hemodialysis (HD) patients. We examined the effect of iron absorption by FC on the relationship between FGF23 and α-klotho. There have been few clinical studies evaluating these biomarkers simultaneously in HD patients. Methods The ASTRIO study was a 24-week, randomized, open-label, multicenter trial. HD patients taking non-iron-based phosphate binder(s) were randomized at a 1:1 ratio to continue other binder(s) (control group) or switch to FC (FC group). Serum phosphate (P) and hemoglobin (Hb) were maintained within 3.5–6.0 mg/dL and 10–12 g/dL, respectively. Plasma levels of intact FGF23 (i-FGF23), C-terminal FGF23 (c-FGF23), and α-klotho were measured, as were iron-related parameters. Association analyses of FGF23 and α-klotho were conducted. Results Patients were randomized to FC (n = 48) and control (n = 45) groups. Serum ferritin significantly increased from baseline to end-of-treatment (EOT) in the FC group, compared with the control group (adjusted mean difference [95% confidence interval]: 79.5 [44.7, 114.4] ng/mL; p

Abstract Background Enhanced oxidative stress is involved with fatigue in hemodialysis (HD) patients. Molecular hydrogen (H2) could improve the redox status. Thus, the study examines whether HD solution rendered by electrolyzed water containing H2 (E-HD) could impact the fatigue and autonomic balance of patients. Methods This single-arm, prospective observational study examined 95 patients on chronic HD (54 males; mean age and HD duration; 71.4 years and 10.6 years). Fatigue status on HD and HD-free days was compared between control HD (CHD) and 8 weeks after commencement of E-HD, using a visual analog scale (VAS) and an original scale. Autonomic balance was analyzed with the degree of activities of the sympathetic and parasympathetic nervous system via frequency analysis of a continuous beat interval. Results Patients were classified into three groups according to the presence of subjective fatigue during the period of CHD: Group A (40.0%), fatigue only on HD days; Group B (11.6%), presence of fatigue on both HD and HD-free days; and Group C (48.4%), freedom from fatigue. During the 8-week observation period of E-HD, VAS scores were significantly decreased on HD days in Group A, while Group B showed no significant changes in VAS on HD days, but significant decreases on HD-free days. No consistent changes were found in Group C. Significant increases in percentages of patients who reported absence of fatigue were seen in Group A on HD days and in Group B on HD-free days in week 8. Regarding changes in autonomic balance parameters after E-HD commencement, a positive correlation was identified between changes in VAS and autonomic balance in Group A. Conclusion E-HD may ameliorate fatigue in patients with subjective symptoms on HD and HD-free days. The influence of autonomic balance by E-HD and its impact on fatigue needs to be elucidated.

Abstract Background This article is a duplicated publication from the Japanese version of “2019 JSDT Guidelines for Peritoneal Dialysis” with permission from the Japanese Society for Dialysis Therapy (JSDT). This clinical practice guideline (CPG) was developed primarily by the Working Group on Revision of Peritoneal Dialysis (PD) Guidelines of the Japanese Society for Dialysis Therapy. Recently, the definition and creation process for CPGs have become far more rigorous; traditional methods and formats no longer adhere to current standards. To improve the reliability of international transmission of our findings, CPGs are created in compliance with the methodologies developed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) working group. Part 2 of this PD guideline is the first CPG developed by our society that conforms to the GRADE approach. Methods Detailed processes were created in accordance with the Cochrane handbook and the GRADE approach developed by the GRADE working group. Results Clinical question (CQ)1: Is the use of renin-angiotensin system inhibitors (RAS inhibitors), such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), effective in PD patients? Recommendation: We suggest the usage of RAS inhibitors (ACEI and ARB) in PD patients (GRADE 2C). CQ2: Icodextrin or glucose solution: which is more useful as a dialysate among patients with PD? Recommendation: We suggest using icodextrin when managing body fluids in PD patients (GRADE 2C). CQ3: Is it better to apply or not apply mupirocin/gentamicin ointment to the exit site? Recommendation: We suggest not applying mupirocin/gentamicin ointment to the exit sites of PD patients (GRADE 2C). CQ4: Which surgical approach is more desirable when a PD catheter is placed, open surgery or laparoscopic surgery? No recommendation. CQ5: Which administration route of antibiotics is better in PD patients with peritonitis, intravenous or intraperitoneal? Recommendation: We suggest intraperitoneal administration of antibiotics in PD patients with peritonitis (GRADE 2C). Note: The National Insurance does not currently cover intraperitoneal administration. CQ6: Is peritoneal dialysis or hemodialysis better as the first renal replacement therapy in diabetic patients? No recommendation. Conclusions In the future, we suggest that society members construct their own evidence to answer CQs not brought up in this guideline, and thereby show the achievements of Japan worldwide.

Abstract Approximately 10 years have passed since the Peritoneal Dialysis Guidelines were formulated in 2009. Much evidence has been reported during the succeeding years, which were not taken into consideration in the previous guidelines, e.g., the next peritoneal dialysis PD trial of encapsulating peritoneal sclerosis (EPS) in Japan, the significance of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), the effects of icodextrin solution, new developments in peritoneal pathology, and a new international recommendation on a proposal for exit-site management. It is essential to incorporate these new developments into the new clinical practice guidelines. Meanwhile, the process of creating such guidelines has changed dramatically worldwide and differs from the process of creating what were “clinical practice guides.” For this revision, we not only conducted systematic reviews using global standard methods but also decided to adopt a two-part structure to create a reference tool, which could be used widely by the society’s members attending a variety of patients. Through a working group consensus, it was decided that Part 1 would present conventional descriptions and Part 2 would pose clinical questions (CQs) in a systematic review format. Thus, Part 1 vastly covers PD that would satisfy the requirements of the members of the Japanese Society for Dialysis Therapy (JSDT). This article is the duplicated publication from the Japanese version of the guidelines and has been reproduced with permission from the JSDT.

Abstract Background A novel hemodialysis (HD) system employing electrolyzed water containing molecular hydrogen (E-HD) has been developed to improve the bio-compatibility of HD. This study examined the impact of E-HD on changes in redox state during HD and HD-related fatigue. Method This single-arm, prospective observational study examined 63 patients on chronic HD (41 males; mean age, 72 ± 9 years; median duration of HD, 7 years). Redox parameters (serum myeloperoxidase [MPO], malondialdehyde-protein adduct [MDA-a], thioredoxin 1 [TRX]) during HD were compared between control HD (C-HD) and E-HD after 8 weeks. Fatigue was evaluated using a numerical rating scale (NRS) during the 8-week course. Results In C-HD, an increase in serum MPO accompanied increases in both oxidative products (MDA-a) and anti-oxidant molecules (TRX). In E-HD, although increases in MPO were accentuated during HD, changes in MDA-a and TRX were ameliorated as compared with C-HD. In patients who showed HD-related fatigue (47%) during C-HD, change in MDA-a by HD was a risk factor for the presence of fatigue. During the 8 weeks of observation on E-HD, those patients displayed significant decreases in fatigue scores. Conclusion E-HD ameliorates oxidative stress and supports anti-oxidation during HD, suggesting improved bio-compatibility of the HD system. E-HD may benefit patients with HD-related fatigue, but the mechanisms underlying changes to oxidative stress have yet to be clarified.

Current periodontal treatment focuses on the mechanical removal of the source of infection, such as bacteria and their products, and there is no approach to control the host inflammatory response that leads to tissue destruction. In order to control periodontal inflammation, we have previously reported the optimization of (+)-terrein synthesis methods and the inhibitory effect of (+)-terrein on osteoclast differentiation in vitro. However, the pharmacological effect of (+)-terrein in vivo in the periodontitis model is still unknown. In this study, we investigated the effect of synthetic (+)-terrein on inflammatory bone resorption using a ligature-induced periodontitis mouse model. Synthetic (+)-terrein (30 mg/kg) was administered intraperitoneally twice a week to the mouse periodontitis model. The control group was treated with phosphate buffer. One to two weeks after the induction of periodontitis, the periodontal tissues were harvested for radiological evaluation (micro-CT), histological evaluation (HE staining and TRAP staining), and the evaluation of inflammatory cytokine production in the periodontal tissues and serum (quantitative reverse-transcription PCR, ELISA). The synthetic (+)-terrein-treated group suppressed alveolar bone resorption and the number of osteoclasts in the periodontal tissues compared to the control group (p < 0.05). In addition, synthetic (+)-terrein significantly suppressed both mRNA expression of TNF-α in the periodontal tissues and the serum concentration of TNF-α (both p < 0.05). In conclusion, we have demonstrated that synthetic (+)-terrein abrogates alveolar bone resorption via the suppression of TNF-α production and osteoclast differentiation in vivo. Therefore, we could expect potential clinical effects when using (+)-terrein on inflammatory bone resorption, including periodontitis.

Abstract The traditional anion gap (AG) equation is widely used, but its misdiagnosis in end-stage kidney disease (ESKD) patients has not been investigated fully. Diagnostic accuracy to detect high AG was cross-sectionally evaluated using 3 AG equations in 1733 ESKD patients with an eGFR less than 15 mL/min/1.73 m2. The prevalence of high AG was 67.9%, 92.1% and 97.4% by the traditional, albumin-adjusted AG (aAG) and full AG equations, respectively. The sensitivity, specificity, accuracy and Kappa coefficient obtained with the traditional AG vs aAG equation were 0.70 vs 0.94, 0.98 vs 0.93, 0.7 vs 0.94, and 0.103 vs 0.44, respectively. Next, we created a subcohort comprising only patients with high full AG and investigated how the traditional AG equation leads to misdiagnoses. Multivariable-adjusted regression analysis in 1688 patients revealed that independent factors associated with a false-negative AG diagnosis were ARB use, eGFR, blood leukocyte count, serum chloride, bicarbonate, ionized calcium, potassium, albumin and phosphate. 93.2% of our subcohort prescribed any of RAAS inhibitors, Loop diuretics or Alkali which could increase either serum chloride or bicarbonate. Frequent use of these possible AG-reducing medications may conceal high AG state in patients with ESKD unless they have incidental inflammation which may increase AG value.

Abstract Background Complications of acute kidney injury (AKI) are common in patients with coronavirus disease in 2019 (COVID-19). However, clinical characteristics of COVID-19-associated AKI are poorly described. We present two cases of severe COVID-19 patients with AKI. Case presentation A 77-year-old woman was suspected of having vancomycin-associated AKI, and a 45-year-old man was suspected of having heme pigment-induced AKI caused by rhabdomyolysis. The granular cast, which is known to be a valuable diagnostic tool for confirming the diagnosis of acute tubular necrosis, was detected in both patients at the onset of AKI. Interestingly, both patients also developed microscopic hematuria at the occurrence of AKI, and one patient had elevated d-dimer and low platelet levels simultaneously. Conclusions Some reports suggested that COVID-19-associated microangiopathy contributed to the kidney damage. Therefore, it is possible that our patients might have accompanied renal microangiopathy, and that this pathological background may have caused exaggerated tubular damage by vancomycin or heme pigment. The etiology of AKI in patients with COVID-19 is multifactorial. Superimposition of nephrotoxin(s) and virus-associate intra-renal microangiopathy may be a crucial trigger of kidney injury leading to severe AKI in COVID-19 patients. Therefore, in COVID-19 patients, risk factors for AKI should be taken into consideration to prevent its progression into severe AKI.

Abstract Biocompatibility of hemodialysis (HD) systems have been considerably improved. However, mortality and morbidity rates of patients have remained high, raising questions regarding the biocompatibility of current systems. In the present study, 70 patients on regular HD (51 males; mean age, 63 years; median duration of HD, 18 months) with high-performance membrane (polysulfone, 77%; polymethylmethacrylate, 23%) at Tohoku University Hospital were examined. Blood samples before and after HD, were subjected to measure apoptosis cells of white blood cells, plasma levels of the following molecules: myeloperoxidase (MPO), pentraxin 3 (PTX3), angiogenin, complements, and 17 cytokines. The main findings were as follows: significant decreases in leukocyte counts by dialysis, significant increases in apoptosis-positive leukocytes by dialysis (neutrophils and monocytes), and significant decrease in plasma angiogenin accompanying increase in plasma MPO and PTX3 levels, with no or only marginal changes in plasma pro-inflammatory cytokine levels and complement products by dialysis. The findings underlined the unsolved issue of bio-incompatibility of HD systems, and suggest the possible pathology of neutrophil apoptosis accompanying MPO release for the development of microinflammation in patients on HD.

Abstract Background Several studies have reported that lower body mass index (BMI) is associated with high mortality in patients with chronic kidney disease (CKD). Rate of infection-related death in CKD patients is increasing. However, the relationship between BMI and infection-related death is unclear. Methods Overall, 2648 CKD outpatients (estimated glomerular filtration rate

The etiology of hyponatremia is assessed based on urine osmolality and sodium. We herein describe a 35-year-old Asian man with pulmonary tuberculosis and perforated duodenal ulcer who presented with hyponatremia with hourly fluctuating urine osmolality ranging from 100 to 600 mosmol/kg, which resembled urine osmolality observed in typical polydipsia and SIADH simultaneously. Further review revealed correlation of body temperature and urine osmolality. Since fever is a known non-osmotic stimulus of ADH secretion, we theorized that hyponatremia in this patient was due to transient ADH secretion due to fever. In our case, empiric exogenous glucocorticoid suppressed transient non-osmotic ADH secretion and urine osmolality showed highly variable concentrations. Transient ADH secretion-related hyponatremia may be underrecognized due to occasional empiric glucocorticoid administration in patients with critical illnesses. Repeatedly monitoring of urine chemistries and interpretation of urine chemistries with careful review of non-osmotic stimuli of ADH including fever is crucial in recognition of this etiology.

Abstract Prolonged peritoneal dialysis (PD) is responsible for progressive morphological changes such as deterioration of the peritoneal membrane. These changes increase the risk of encapsulating peritoneal sclerosis (EPS). Histological assessments of peritoneal membrane biopsy samples are fundamental for the evaluation of the peritoneal damage caused by PD. For evaluating serial morphological changes induced in the peritoneum by PD, we recommend to perform peritoneal biopsy examinations not only after the cessation of PD but also before performing PD. At the time of PD catheter insertion, the parietal peritoneum (1.5 × 1.5 cm) and rectus abdominal muscle posterior sheath is sampled at a point 3 cm below the PD catheter insertion site. Furthermore, at the time of PD catheter removal, the parietal peritoneum is sampled at a point 3 cm apart from the PD catheter insertion site to avoid artifacts. The peritoneum should be evaluated to detect mesothelial cell denudation, acellular sclerotic changes and thickness of the submesothelial connective tissue, vasculopathy of the post-capillary venules, vascular angiogenesis, and new encapsulating membrane. The method presented herein allows the minimization of surgical invasiveness and artifacts of the specimens and safe performance of peritoneal biopsy examinations. Morphological evaluation of the peritoneum involving an appropriate biopsy strategy, in conjunction with functional markers of deterioration, such as peritoneal permeability or cytokine levels, is a useful approach for examining peritoneal damage and predicting the prognosis of PD patients, especially the onset of EPS.

Background Higher serum β2-microglobulin (B2M) concentrations are associated with higher mortality in the general population, non-dialyzed chronic kidney disease patients and patients receiving hemodialysis (HD). However, this relationship among patients on peritoneal dialysis (PD) has not been validated. Methods We collected baseline data for 3,011 prevalent PD patients from a nationwide dialysis registry in Japan at the end of 2010. Clinical outcomes for 9 years were then evaluated using the registry at the end of 2011 to 2019. All-cause and cardiovascular (CV) mortality was assessed using Cox regression analysis and competing-risks regression analysis, respectively. We used multiple imputation to deal with missing covariate data. Results During a median follow-up of 87 months, 2,054 patients transferred to combined therapy with PD and HD or HD directly. A total of 3,011 patients, 1,235 (41.0%) died, including 437 patients (14.5%) from CV causes. Among them, 612 patients died after transfer to other dialysis modalities. Univariate analyses revealed no significant association between serum B2M and mortality, whereas higher serum B2M was independently associated with both all-cause and CV mortalities in adjusted models. However, the significant association between serum B2M and CV mortality disappeared in analysis treating serum B2M as a categorical variable. The effect of serum B2M on all-cause mortality was significantly higher among patients with higher urinary volume and a significant interaction was evident. Conclusions Using a large-scale registry, we found that serum B2M contributes tenuously but significantly to worse outcome and residual kidney function significantly affects this relationship. On the contrary, serum B2M per se had no predictive value for patient outcome in prevalent PD patients.

Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-κB ligand (RANKL)–induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKCα/βII, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis.

Abstract Background Ferritin is a well-known marker of iron deficiency anemia, but the target in maintenance hemodialysis (MHD) patients remains controversial. This study examined the association between baseline ferritin levels and clinical outcomes. Methods We retrospectively collected the data of outpatients on MHD for 5 years at St. Luke’s International Hospital from July 2009. Patients with baseline ferritin levels of > 100 ng/mL in June 2009 were defined as the high-ferritin (HF) group and the remaining patients as the low-ferritin (LF) group. The primary endpoint was all-cause mortality. The secondary endpoints included cardiovascular events and infection-related hospitalizations. Log-rank test and Cox proportional hazard analysis were performed. Results Of 116 patients (age, 65.4 ± 13.4 years, 70% males), 29 (25%) and 87 (75%) belonged to the HF and LF groups, respectively. During the follow-up period of 1825 (interquartile range 819–1825) days, 38 patients (23 in the HF and 15 in the LF groups) died. According to the Kaplan–Meier survival curves, the HF group had significantly poor survival compared with the LF group (p = 0.0089). After adjusting for age, sex, vintage of hemodialysis, C-reactive protein levels, and history of cardiovascular events, the hazard ratio (HR) for the HF group was 2.49 (95% confidence interval (CI), 1.21–5.12). The multivariate analysis of cardiovascular events revealed a similar result with statistical significance (HR 2.69; 95% CI 1.12–6.46). Infection-related hospitalizations did not exhibit any statistically significant difference. Conclusions In MHD patients, ferritin levels > 100 ng/mL is associated with increased rates of all-cause mortality and cardiovascular events.

Abstract Background At least 2.6 million adults and children receive dialysis treatment for end-stage kidney disease (ESKD) worldwide. The large majority of these receive hemodialysis (HD), while the remaining receive peritoneal dialysis (PD). Peritoneal dialysis may be associated with similar mortality outcomes as HD, and patient-reported outcomes are potentially increased with PD. Existing evidence for the mortality associated with PD was summarized over 20 years ago, and there has been greater marginal improvement in survival with PD relative to HD since that time. It is therefore timely to reexamine the question of differential mortality by modality and summarize evidence from more contemporary practice settings. Methods/design Electronic databases will be systematically searched for publications that report the association between dialysis modality (HD or PD) with death from any cause and cause-specific death in incident patients with end-stage kidney disease. The database searches will be supplemented by searching through citations and references and consultation with experts. Studies published before 1995 will be excluded. Screening of both titles and abstracts will be done by two independent reviewers. All disagreements will be resolved by an independent third reviewer. A quantitative meta-analysis of effect sizes and standard errors will be applied. Discussion Our systematic review will update previous evidence summaries and provide a quantitative and standardized assessment of the contemporary literature comparing HD and PD including published and unpublished non-English studies from greater China, Taiwan, and Japan. This review will inform shared decision-making around initial dialysis modality choice and jurisdiction-level considerations of dialysis practice. Systematic review registration PROSPERO CRD42018111829

One third of the patients with chronic kidney disease (CKD) develop cognitive impairment, which is also an independent risk factor for mortality. However, the concise mechanism of cerebro-renal interaction has not been clarified. The present study examines the effects of uremic toxins on neuronal cells and analyzes the pathological condition of the brain using mouse hippocampal neuronal HT-22 cells and adenine-induced CKD model rats. Among the uremic toxins analyzed, indoxyl sulfate, indole, 3-indoleacetate, and methylglyoxal significantly decreased viability and glutathione level in HT-22 cells. The mixture of these uremic toxins also decreased viability and glutathione level at a lower dose. Adenine-induced CKD rat showed marked renal damage, increased urinary oxidative stress markers, and increased numbers of pyknotic neuronal cells in hippocampus. CKD rats with damaged hippocampus demonstrated poor learning process when tested using the Morris water maze test. Our results suggest that uremic toxins have a toxic effect on hippocampal neuronal cells and uremic CKD rats shows pyknosis in hippocampus.

BackgroundFatigue is one of the most frequent complications in dialyzed patients and is associated with poorer patient outcomes. Multiple factors are reported to be associated with fatigue development. Of them, the impacts of dialysis modalities remain unknown.MethodsA total of 194 dialysis patients (mean age, 61±11 years; 134 males; modalities included hemodialysis (HD) in 26, online hemodiafiltration (HDF) in 74, peritoneal dialysis (PD) in 68, and combined therapy with PD and HD in 26 cases) were recruited for this cross-sectional study. Fatigue was assessed using the Profile of Mood States (POMS), a Visual Analogue Scale (VAS), and our original scale of fatigue, and depression was assessed by the Beck Depression Inventory-second edition (BDI-II). Our original scale of fatigue was administered both on dialysis and dialysis-free days to patients on HD and online HDF.ResultsThe scores of the POMS, VAS, and our original scale were weakly but significantly inter-related (rho = 0.58, PConclusionsThe results suggest that there is no significant association between different dialysis modalities including HD, online HDF, PD and combined therapy with PD and HD and the prevalence or severity of fatigue.

BackgroundHyperuricemia is highly prevalent in chronic kidney disease (CKD) patients, but the evidence for a relationship between uric acid (UA) and clinical outcomes in CKD patients is limited and inconsistent. We hypothesized that UA has a different impact on clinical outcomes according to the underlying disease causing CKD.MethodsThis study prospectively investigated the associations between UA and renal and non-renal outcomes according to the underlying disease causing CKD in 2,797 Japanese patients under the care of nephrologists. The patients were categorized into four groups: primary renal disease (n = 1306), hypertensive nephropathy (n = 467), diabetic nephropathy (n = 275), and other nephropathy (n = 749). The renal outcome was defined as end-stage renal disease (ESRD), and the non-renal outcome was defined as a composite endpoint of cardiovascular events (CVEs) and all-cause mortality.ResultsDuring a median 4.8-year follow-up, 359 (12.8%) patients reached the renal outcome, and 260 (9.3%) reached the non-renal outcome. In the all-patient analysis, hyperuricemia was not associated with the risks for renal and non-renal outcomes, but in primary renal disease (PRD) and hypertensive renal disease (HTN) patients, hyperuricemia was significantly associated with non-renal outcomes. Per 1 mg/dl higher UA level, multivariable adjusted hazard ratio was 1.248 (95% CI: 1.003 to 1.553) for PRD, and 1.250 (1.035 to 1.510) for HTN. Allopurinol did not reduce the risks for renal and non-renal outcomes, both in all patients and in the subgroup analysis.ConclusionsThe effect of hyperuricemia on clinical outcomes in CKD patients varies according to the underlying disease causing CKD. Hyperuricemia is an independent risk factor for non-renal outcomes in primary renal disease and hypertensive renal disease patients. Allopurinol did not decrease the risks for renal and non-renal outcomes.

Abstract Background The definition and guideline of sepsis and septic shock were recently updated. The aim of this study is to evaluate the ability of Third Consensus Definitions of Sepsis and Septic Shock (Sepsis-3) to predict outcomes among patients with community-acquired sepsis receiving continuous renal replacement therapy (CRRT). Methods We conducted a retrospective observational study between January 2013 and December 2015 in a single university hospital. From 368 patients receiving CRRT for various reasons, 64 patients who suffered from community-acquired sepsis and required CRRT were selected and evaluated using the current and previous sepsis criteria. We additionally assessed infection characteristics. The primary outcome was 28-day mortality, and the secondary outcome was in-hospital mortality. Results Of the 64 participants (70.3% male, median age 66.5 years), 33 (51.6%) administered antimicrobials before admission. The most common source of infections was pneumonia, and 27 participants (42.2%) had positive cultures. The Sepsis-3 criteria identified 64 cases (100%) as sepsis at the start of CRRT, while the previous criteria identified 44 cases (68.8%). According to the Sepsis-3 criteria, the 28-day mortality of sepsis and septic shock were 31.3% (20/64) and 46% (17/37), and in-hospital mortality was 43.8% (28/64) and 62.2% (23/37), respectively. Septic shock diagnosed using the Sepsis-3 criteria predicted mortality (log-rank P = 0.0001); however, using the previous criteria was not associated with mortality (log-rank P = 0.437). Among variables, lactate levels ≥ 2 mmol/L and SOFA score ≥ 14 were significantly associated with mortalities, with an optimal cutoff value for lactate of 1.8 mmol/L (AUC 0.777, sensitivity 85.7%, specificity 58.3%). Although age ≥ 65 years predicted in-hospital mortality, and pre-hospital antimicrobial therapy tended to be associated with 28-day mortality, we did not detect any association between outcomes and the CRRT regimen or general risk factors (e.g., acute kidney injury, serum creatinine levels, and comorbidities). Conclusions Our data suggests that the Sepsis-3 criteria predicted survival more accurately than the previous criteria among patients with community-acquired sepsis receiving CRRT. This is based on lactate levels and SOFA scores being strongly associated with mortality.

A recent study suggested that orally dosed ferric citrate hydrate (FC) corrects renal anemia in patients on hemodialysis (HD), suggesting biological differences in effects of iron supplementation using different routes of administration. To address this issue, the present study compared oral FC with i.v. saccharated ferric oxide (FO) in stable HD patients. Methods: Participants comprised 6 patients administered 3 consecutive protocols in the first HD session of the week in a fasting state: nothing given, as control (C); oral load of FC (480 mg iron), and 5 minutes of i.v. FO (40 mg iron). Iron dynamics in the body and biological impact on redox-inflammation status during the study (6 hours) were examined. Results: Significant increases in serum iron and transferrin saturation were seen with both FC and FO. Regarding total iron-binding capacity as the sum of serum iron and unsaturated iron-binding capacity, no changes were found in FC, whereas significant increases were seen in FO (appearance of non–transferrin-binding iron [NTBI]), despite the lower serum iron levels in FO. Compared with C, increases were seen in serum myeloperoxidase (oxidative marker) with accompanying significant decreases in thioredoxin (antioxidant) in FO, whereas no changes were found in FC. Conclusion: Oral FC differs from i.v. FO in areas such as less NTBI generation and less induction of oxidative stress. The result indicates potential clinical benefits of oral FC in terms of iron supplementation for renal anemia in HD patients.

Abstract Recent studies have revealed unique biological characteristics of molecular hydrogen (H2) as an anti-inflammatory agent. We developed a novel haemodialysis (E-HD) system delivering an H2 (30–80 ppb)-enriched dialysis solution by water electrolysis, and conducted a non-randomized, non-blinded, prospective observational study exploring its clinical impact. Prevalent chronic HD patients were allocated to either the E-HD (n = 161) group or the conventional HD (C-HD: n = 148) group, and received the respective HD treatments during the study. The primary endpoint was a composite of all-cause mortality and development of non-lethal cardio-cerebrovascular events (cardiac disease, apoplexy, and leg amputation due to peripheral artery disease). During the 3.28-year mean observation period, there were no differences in dialysis parameters between the two groups; however, post-dialysis hypertension was ameliorated with significant reductions in antihypertensive agents in the E-HD patients. There were 91 events (50 in the C-HD group and 41 in the E-HD group). Multivariate analysis of the Cox proportional hazards model revealed E-HD as an independent significant factor for the primary endpoint (hazard ratio 0.59; [95% confidence interval: 0.38–0.92]) after adjusting for confounding factors (age, cardiovascular disease history, serum albumin, and C-reactive protein). HD applying an H2-dissolved HD solution could improve the prognosis of chronic HD patients.

Porphyromonas gingivalis (P. gingivalis) is a major oral pathogen and associated with periodontal diseases including periodontitis and alveolar bone loss. In this review, we indicate that two virulence factors, which are hemoglobin receptor protein (HbR) and cysteine proteases “gingipains”, expressed by P. gingivalis have novel functions on the pathogenicity of P. gingivalis. P. gingivalis produces three types of gingipains and concomitantly several adhesin domains. Among the adhesin domains, hemoglobin receptor protein (HbR), also called HGP15, has the function of induction of interleukin-8 (IL-8) expression in human gingival epithelial cells, indicating the possibility that HbR is associated with P. gingivalis-induced periodontal inflammation. On bacteria-host cells contact, P. gingivalis induces cellular signaling alteration in host cells. Phosphatidylinositol 3-kinase (PI3K) and Akt are well known to play a pivotal role in various cellular physiological functions including cell survival and glucose metabolism in mammalian cells. Recently, we demonstrated that gingipains attenuate the activity of PI3K and Akt, which might have a causal influence on periodontal diseases by chronic infection to the host cells from the speculation of molecular analysis. In this review, we discuss new molecular and biological characterization of the virulence factors from P. gingivalis.

Abstract Background Peritoneal dialysis (PD) is used as renal replacement therapy in patients with end-stage kidney disease. However, peritoneal membrane failure remains problematic and constitutes a critical cause of PD discontinuation. Recent studies have revealed the unique biological action of molecular hydrogen (H2) as an anti-oxidant, which ameliorates tissue injury. In the present study, we aimed to examine the effects of H2 on the peritoneal membrane of experimental PD rats. Method Eight-week-old male Sprague-Dawley rats were divided into the following groups (n = 8–11 each) receiving different test solutions: control group (no treatment), PD group (commercially available lactate-based neutral 2.5% glucose PD solution), and H2PD group (PD solution with dissolved H2 at 400 ppb). Furthermore, the influence of iron (FeCl3: 5 μM: inducer of oxidative cellular injury) in the respective PD solutions was also examined (Fe-PD and Fe-H2PD groups). The H2PD solution was manufactured by bathing a PD bag in H2-oversaturated water created by electrolysis of the water. Twenty mL of the test solutions were intraperitoneally injected once a day for 10 days. Parietal peritoneum samples and cells collected from the peritoneal surface following treatment with trypsin were subjected to analysis. Results In the PD group as compared to controls, a mild but significant sub-mesothelial thickening was observed, with increase in the number of cells in the peritoneal surface tissue that were positive for apoptosis, proliferation and vimentin, as seen by immunostaining. There were significantly fewer of such changes in the H2PD group, in which there was a dominant presence of M2 (CD163+) macrophages in the peritoneum. The Fe-PD group showed a significant loss of mesothelial cells with sub-mesothelial thickening, these changes being ameliorated in the Fe-H2PD group. Conclusion H2-dissolved PD solutions could preserve mesothelial cells and peritoneal membrane integrity in PD rats. Clinical application of H2 in PD could be a novel strategy for protection of peritoneal tissue during PD treatment.

Abstract Background Newly formed membrane (NFM) on the peritoneal membrane proper is a unique pathological hallmark of encapsulating peritoneal sclerosis (EPS), but its definition and diagnostic significance have not been well described. This study investigated the pathological features of NFM in EPS and prevalence of NFM in peritoneal biopsy at catheter removal. Methods This multicenter retrospective, observational study was conducted by the Japanese Society of Peritoneal Dialysis and enrolled ten patients with and 52 without EPS at peritoneal biopsy during enterolysis surgery or catheter removal. All patients were treated using conventional, acidic peritoneal dialysis (PD) solutions. Thirty of the 52 non-EPS patients perform peritoneal lavage once daily after completing PD to prevent the development of EPS and 22 discontinued PD without lavage. NFM was defined as additional membrane structure on the peritoneum that is properly characterized by exudative or fibrous matrices and fibroblast-like cells. Immunostaining of fibrin and podoplanin was performed for the evaluation of NFM. Results NFM was confirmed histologically in eight of the ten patients with EPS. It was also detected in 13 of the 30 patients (43.3%) in the post-PD lavage group and in one of the 22 patients (4.5%) in the non-lavage group. The NFM histology showed various stages of EPS pathology, from early exudative changes with fibrin deposition (stage I; n = 5), progressing to proliferative and fibrosing changes with podoplanin-positive fibroblast-like cells (stage II; n = 9), and finally resulting in adhesive and fibrous scar formation (stage III; n = 8). Immunostaining of fibrin and podoplanin was helpful for evaluating the stage of the NFM. Conclusions NFM contributes the encapsulation of intestines and is a pathological hallmark of EPS, but can be detected microscopically in patients without EPS, especially those with peritoneal lavage after PD. New membrane formation starts insidiously in peritoneal membrane damaged by PD treatment, but does not necessarily lead to the development of EPS.

In hemodialysis patients on ferric citrate hydrate, the increase in ferritin level is mainly due to the administration of the compound. We investigated possible other factors associated with ferritin level and how erythropoietin resistance index and erythropoiesis in those patients were affected. We looked at ferritin-elevating factors using data from a Japanese phase III long-term clinical trial of ferric citrate hydrate. Methods: The factors with a strong association with ferritin levels at week 28 were selected by the process of variable selection. In addition, selected factors were analyzed by Mixed Model for Repeated Measurement. Subjects were divided into 3 groups by quantiles (

Uremic toxins are suggested to be involved in the pathophysiology of hemodialysis (HD) patients. However, the profile of uremic solutes in HD patients has not been fully elucidated. In this study using capillary electrophoresis mass spectrometry (CE-MS), we comprehensively quantified the serum concentrations of 122 ionic solutes before and after HD in 11 patients. In addition, we compared the results with those in non-HD patients with chronic kidney disease (CKD) to identify HD patient-specific solutes. We identified 38 solutes whose concentrations were higher in pre-HD than in CKD stage G5. Ten solutes among them did not significantly accumulate in non-HD CKD patients, suggesting that these solutes accumulate specifically in HD patients. We also identified 23 solutes whose concentrations were lower in both pre- and post-HD than in CKD stage G5. The serum levels of 14 solutes among them were not affected by renal function in non-HD patients, suggesting that these solutes tend to be lost specifically in HD patients. Our data demonstrate that HD patients have a markedly different profile of serum uremic solute levels compared to that in non-HD CKD patients. The solutes identified in our study may contribute to the pathophysiology of HD patients.

Control of bacterial infection-induced inflammatory responses is one of the effective therapeutic approaches of periodontal diseases. Natural products such as lipid mediators and metabolites from microorganisms have been used for decreasing inflammation. We previously reported that (+)-terrein inhibited activation of STAT3 and ERK1/2 in interleukin-6 (IL-6) signaling cascade, leading to prevent vascular endothelial growth factor (VEGF) secretion in human gingival fibroblasts (HGFs). However, little is still known about the role of (+)-terrein on inflammatory responses. In this study, we provided the possibility of novel action that (+)-terrein inhibits activation of Janus-activated kinase 1 (JAK1), which has a central function in IL-6 signaling cascade, and alters expression of mRNAs and proteins induced by IL-6/soluble IL-6 receptor (sIL-6R) stimulation in HGFs. First, we performed PCR array to examine IL-6/sIL-6R-induced mRNA expression, and then expression of mRNA and protein of colony stimulating factor-1 (CSF1) and VEGF were clearly determined by quantitative RT-PCR and ELISA, respectively. Treatment with (+)-terrein suppressed expression of mRNA and protein of CSF1 and VEGF by IL-6/sIL-6R stimulation. Next, to test the effect of (+)-terrein on IL-6/sIL-6R signaling cascade, we demonstrated whether (+)-terrein affects phosphorylation of JAK1 and its downstream proteins, Akt and SHP-2. Western blotting revealed that (+)-terrein inhibited IL-6/sIL-6R-induced phosphorylation of JAK1, Akt, and SHP-2. Therefore, (+)-terrein suppresses IL-6/sIL-6R-induced expression of CSF1 and VEGF via inhibition of JAK1, Akt, and SHP-2. Based on our results, we suggest that (+)-terrein is a candidate compound for anti-inflammatory effect associated with IL-6 signaling.

It is supposed that enhanced oxidative stress and inflammation are involved with the poor clinical outcomes in patients on chronic dialysis treatment. Recent studies have shown that molecular hydrogen (H2) is biologically active as an anti-inflammatory agent. Thus, we developed a novel hemodialysis (E-HD) system which delivers H2 (30 to 80 ppb)-enriched dialysis solution, to conduct a prospective observational study (UMIN000004857) in order to compare the long-term outcomes between E-HD and conventional-HD (C-HD) in Japan. The present interim analysis aimed to look at potential clinical effects of E-HD during the first 12 months observation.262 patients (140, E-HD; 122, C-HD) were subjected for analysis for comprehensive clinical profiles. They were all participating in the above mentioned study, and they had been under the respective HD treatment for 12 consecutive months without hospitalization. Collected data, such as, physical and laboratory examinations, medications, and self-assessment questionnaires on subjective symptoms (i.e., fatigue and pruritus) were compared between the two groups.In a 12-month period, no clinical relevant differences were found in dialysis-related parameters between the two groups. However, there were differences in the defined daily dose of anti-hypertensive agents, and subjective symptoms, such as severe fatigue, and pruritus, which were all less in the E-HD group. Multivariate analysis revealed E-HD was an independent significant factor for the reduced use of anti-hypertensive agents as well as the absence of severe fatigue and pruritus at 12 months after adjusting for confounding factors.The data indicates E-HD could have substantial clinical benefits beyond conventional HD therapy, and support the rationale to conduct clinical trials of H2 application to HD treatment.

Methylglyoxal (MG), one of the uremic toxins, is a highly reactive alpha-dicarbonyl compound. Recent clinical studies have demonstrated the close associations of cognitive impairment (CI) with plasma MG levels and presence of kidney dysfunction. Therefore, the present study aims to examine whether MG is a direct causative substance for CI development. Eight-week-old male Sprague-Dawley (SD) rats were divided into two groups: control (n = 9) and MG group (n = 10; 0.5% MG in drinking water), and fed a normal diet for 12 months. Cognitive function was evaluated by two behavioral tests (object exploration test and radial-arm maze test) in early (4–6 months of age) and late phase (7–12 months of age). Serum MG was significantly elevated in the MG group (495.8 ± 38.1 vs. 244.8 ± 28.2 nM; p < 0.001) at the end of study. The groups did not differ in cognitive function during the course of study. No time-course differences were found in oxidative stress markers between the two groups, while, antioxidants such as glutathione peroxidase and superoxide dismutase activities were significantly increased in the MG group compared to the control. Long-term MG administration to rats with normal kidney function did not cause CI. A counter-balanced activation of the systemic anti-oxidant system may offset the toxicity of MG in this model. Pathogenetic significance of MG for CI requires further investigation.