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ABSTRACT Aims/Introduction To conduct a multicenter survey of visually impaired patients with diabetes mellitus (DM) and to identify the physical and ocular characteristics that lead to blindness in Japan. Materials and Methods Visually impaired patients with diabetes mellitus in Japan were divided into blind and low‐vision groups according to the World Health Organization classification. Data on parameters related to diabetes mellitus and ocular complications in the right and left eyes were collected from 19 highly advanced medical facilities and compared between the two groups. Results Among 408 visually impaired persons (blind group: 257, low‐vision group: 151), 72.1% were under 70 years of age. The rates of neovascular glaucoma (NVG) (right eye, P = 0.041; left eye, P = 0.0031) or proliferative diabetic retinopathy (PDR) (right eye: P = 0.014, left eye: P = 0.0047) and the rate of proliferative membrane beyond half of the retinal area (right eye: P = 0.0263, left eye: P = 0.037) were significantly higher in the blind group. The direct cause of visual impairment was retinal atrophy, common in both groups. Neovascular glaucoma and diabetic macular edema were equally prevalent in the blind and low‐vision groups, respectively. Conclusions In Japan, blind patients with diabetes mellitus are characterized by severe conditions such as neovascular glaucoma and progressive proliferative diabetic retinopathy upon their initial visit to an advanced care facility. These results highlight the importance of monitoring retinopathy through regular ophthalmological examinations, internal medicine, and appropriate therapeutic intervention.

Aging is a high-risk factor for obstructive and fibrotic lung diseases. Fibrotic lung disease leading to decreased lung function is characterized by interstitial remodeling and tissue scarring (sclerosis), with destruction of alveoli and excess deposition of type I collagen, an extracellular matrix component secreted by fibroblasts. Therefore, regulating transforming growth factor-β (TGF-β) as a profibrotic signal is essential to suppress pulmonary fibrosis. In pulmonary fibrosis, TGF-β signaling is mediated by Smad and YAP/TAZ, and TAZ linked to the pathology of pulmonary function is observed in lung fibroblasts from patients with idiopathic pulmonary fibrosis. Although fibrosis is thought to be irreversible, it is an interventional condition. Decorin (DCN) blocks TGF-β signaling in pulmonary fibrosis, although there are no cellular pharmacological methods to stimulate DCN secretion. We previously showed that chicken eggshell membrane (ESM, a well-known wound-healing material) promotes dcn gene expression in fibroblasts. In this study, we investigated whether ESM stimulates DCN secretion as an endogenous mediator and ameliorates pulmonary fibrosis. Decorin secretion was significantly enhanced in the WI-38 lung fibroblast culture supernatants supplemented with ESM. This effect was increased with major component lysozyme and maximally promoted in experiments with lysozyme and ovotransferrin (the two main proteins in soluble ESM) at a 16:1 concentration ratio, the ratio in the ESM extract. Decorin secretion by ESM modulates TGF-β signaling in lung fibroblasts by reducing TAZ and pSmad2 nuclear localization. Decorin siRNA experiments confirmed that nuclear localization of TAZ is DCN-dependent. In a mouse model of bleomycin-induced pulmonary fibrosis, all fibrotic markers of ESM treatment group such as hydroxyproline (a collagen deposition marker), and both evaluation of fibrosis density by automated thresholding of picrosirius red-stained lung tissue scan images and Ashcroft fibrosis scores, and also the nuclear localization of TAZ were reduced after 2 weeks compared with control group. Furthermore, long-term (22 week) ESM consumption by healthy individuals significantly improved vital capacity and the forced expiratory volume in 1 s to forced vital capacity ratio (FEV1/FVC). This study reveals that ESM, a well-established wound-healing material, may be a potential preventive medicine for pulmonary fibrosis.

Abstract We investigated the effects of acute-phase intensive electrical muscle stimulation (EMS) on physical function in COVID-19 patients with respiratory failure requiring invasive mechanical ventilation (IMV) in the intensive care unit (ICU). Consecutive COVID-19 patients requiring IMV admitted to a university hospital ICU between January and April 2022 (EMS therapy group) or between March and September 2021 (age-matched historical control group) were included in this retrospective observational case–control study. EMS was applied to both upper and lower limb muscles for up to 2 weeks in the EMS therapy group. The study population consisted of 16 patients undergoing EMS therapy and 16 age-matched historical controls (median age, 71 years; 81.2% male). The mean period until initiation of EMS therapy after ICU admission was 3.2 ± 1.4 days. The EMS therapy group completed a mean of 6.2 ± 3.7 EMS sessions, and no adverse events occurred. There were no significant differences between the two groups in Medical Research Council sum score (51 vs. 53 points, respectively; P = 0.439) or ICU mobility scale at ICU discharge. Addition of upper and lower limb muscle EMS therapy to an early rehabilitation program did not result in improved physical function at ICU discharge in severe COVID-19 patients.

Background: d-alanine administration prevented kidney damage in a murine acute kidney injury model. Further data are needed on the influence of d-alanine on kidney function in humans. Objective: This study investigated the effects of d-alanine intake on amino acid metabolism and kidney function in healthy volunteers. Methods: This multicenter pilot study randomly assigned individuals from the general Japanese population to receive 3 g or 6 g of d-alanine intake per day for 7 d in a 1:1 ratio. The primary endpoint was the mean change in plasma and urine d-alanine levels from baseline to 7 d after intake. The secondary endpoints were mean changes in kidney function and other clinical factors. Safety was assessed by evaluating adverse events and clinical parameters. Results: We randomly assigned 24 participants to the 3-g (n = 12) and 6-g d-alanine (n = 12) groups. The mean baseline estimated glomerular filtration rate (eGFR) was 73 mL/min/1.73 m2. The mean plasma d-alanine concentration increased from baseline by 77.5 ± 34.3 and 192.1 ± 80.9 nmol/mL in the 3-g and 6-g d-alanine groups (both p < 0.0001), respectively, in a dose-dependent manner (between-group difference: 114.6 nmol/mL; 95% CI: 62.1–167.2; P = 0.0002). A similar increase was observed for the urine d-alanine to creatinine ratio. The mean eGFR was elevated by 5.7 ± 8.8 mL/min/1.73 m2 in the 6-g d-alanine group (P = 0.045) but did not significantly change in the 3-g d-alanine group. Nonserious adverse events were reported in 11 participants. Conclusions: d-alanine intake increased plasma and urine d-alanine levels and was well tolerated in participants with normal kidney function. These results will be useful in future trials investigating the effects of d-alanine intake on kidney disease progression in patients with chronic kidney disease.This trial was registered at the UMIN Clinical Trials Registry as UMIN000051466.

ABSTRACT Aims/Introduction This multicenter cohort study retrospectively assessed the association between polar vasculosis and the progression of diabetic kidney disease (DKD) in type 2 diabetes. Materials and Methods We enrolled 811 patients with type 2 diabetes, biopsy‐proven DKD, and proteinuria (≥0.15 g/g creatinine [g/day]). The association between polar vasculosis and other kidney lesions was explored. The outcome was DKD progression defined as a composite of renal replacement therapy initiation or 50% decline in estimated glomerular filtration rate (eGFR) from baseline. Results Of the 811 cases, 677 (83.5%) had polar vasculosis. In multivariate logistic regression analysis, subendothelial widening of the glomerular basement membrane, glomerulomegaly, glomerular class in the Renal Pathology Society classification ≥IIb, vascular lesions, age, eGFR, and hemoglobin A1c were positively associated with polar vasculosis, whereas interstitial fibrosis and tubular atrophy (IFTA) was negatively associated with polar vasculosis. During a median follow‐up of 5.2 years, progression of DKD occurred in 322 of 677 (7.4 events/100 person‐years) and 79 of 134 (11.4 events/100 person‐years) cases with and without polar vasculosis, respectively. Kaplan–Meier analysis showed that polar vasculosis was associated with lower cumulative incidences of DKD progression. Multivariate Cox regression analyses showed that polar vasculosis was associated with a lower risk of DKD progression, regardless of eGFR or proteinuria subgroups. These associations between polar vasculosis and better kidney outcome were unchanged considering all‐cause mortality before DKD progression as a competing event. Conclusions This study showed that polar vasculosis of DKD was associated with less advanced IFTA and a better kidney outcome in type 2 diabetes with proteinuria.

Abstract This prospective observational cohort study was performed to investigate the physical function and mental health trajectories of novel coronavirus disease 2019 (COVID-19) patients requiring invasive mechanical ventilation (IMV) after discharge from the intensive care unit (ICU). The study population consisted of 64 patients (median age, 60 years; 85.9% male; median IMV duration, 9 days). At ICU discharge, 28.1% of the patients had Medical Research Council (MRC) sum score

Abstract Association rule is a transparent machine learning method expected to share information about risks for chronic kidney disease (CKD) among diabetic patients, but its findings in clinical data are limited. We used the association rule to evaluate the risk for kidney disease in General and Worker diabetic cohorts. The absence of risk factors was examined for association with stable kidney function and worsening kidney function. A confidence value was used as an index of association, and a lift of > 1 was considered significant. Analyses were applied for individuals stratified by KDIGO’s (Kidney Disease: Improving Global Outcomes) CKD risk categories. A General cohort of 4935 with a mean age of 66.7 years and a Worker cohort of 2153 with a mean age of 47.8 years were included in the analysis. Good glycemic control was significantly related to stable kidney function in low-risk categories among the General cohort, and in very-high risk categories among the Worker cohort; confidences were 0.82 and 0.77, respectively. Similar results were found with poor glycemic control and worsening kidney function; confidences of HbA1c were 0.41 and 0.27, respectively. Similarly, anemia, obesity, and hypertension showed significant relationships in the low-risk General and very-high risk Worker cohorts. Stratified risk assessment using association rules revealed the importance of the presence or absence of risk factors.

Abstract Background The prognosis of focal segmental glomerulosclerosis patients with nephrotic syndrome is estimated to be 10%–20% in 5 years and 30%–50% in 10 years, leading to end‐stage kidney disease. The response rate with steroid therapy is 40%–60%. Therapeutic low‐density lipoprotein‐apheresis (LDL‐A) may be effective in patients with steroid resistance. Information regarding the long‐term prognosis of patients with focal segmental glomerulosclerosis receiving this therapy is scarce. Methods We investigated the effectiveness of treatment in 50 patients with primary focal segmental glomerulosclerosis diagnosed between 1961 and 2017 at Kanazawa University Hospital and related facilities. The patients were observed at least 12 months after biopsy or until end‐stage kidney disease occurrence or death. Results LDL‐A was performed in four patients who presented with steroid‐resistant nephrotic syndrome (two patients had concurrent acute renal failure for which hemodialysis was performed). In comparison with 17 patients who did not receive LDL‐A after 1989, the LDL‐A group had higher urinary protein excretion (13.7 vs. 5.2 g/day, P = 0.053) and serum creatinine (4.11 vs. 1.65 mg/dL) levels at onset, and a numerically higher remission rate (75.0% vs. 58.7%) compared with the nonlipoprotein‐apheresis group. Conclusion Therapeutic LDL‐A can be performed for critical cases and may improve the remission rate.

Abstract Background This study investigated the sex differences in the risk of end‐stage kidney disease (ESKD) and mortality, as well as the effect modification of sex on associated factors in patients with type 2 diabetes. Methods This multicenter observational cohort study included 4328 patients with type 2 diabetes. Hazard ratios (HRs) with 95% confidence intervals (CIs) of sex for ESKD and death were estimated using Cox proportional regression with adjustment for baseline covariates. For assessing risk modification, HRs and incidence rates for ESKD and death were compared between sexes across patient characteristics using Cox proportional and Poisson regression models. Results During a median follow‐up of 7 years, 276 patients (70% men) developed ESKD, and 241 patients (68% men) died. Men had higher risks of ESKD (HR 1.34; 95% CI 1.02–1.75; p = .034) and death (HR 1.64; 95% CI 1.24–2.16; p = .001) versus women after adjusting for multiple covariates. Among patients with microalbuminuria, men had a substantially higher risk of ESKD versus women, compared to those with normo‐ and macroalbuminuria (p for interaction .04). Incidence rates were also increased in men versus women with albuminuria of around 300 mg/g. No differences were detected in the association of sex and death across baseline patient subgroups. Conclusions In type 2 diabetes, men had an increased risk of ESKD and death versus women. Moderately increased albuminuria was strongly associated with sex difference in developing ESKD.

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.

Abstract 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

Abstract The human being dynamically and highly controls the head–trunk with redundant mechanical structures to maintain a stable upright standing position that is inherently unstable. The posture control strategies are also affected by the differences in the conditions of sensory inputs. However, it is unclear how the head–trunk segmental properties are altered to respond to situations that require appropriate changes in standing posture control strategies. We used a data-driven approach to conduct a multipoint measurement of head–trunk sway control in a quiet standing position with differences in the conditions of sensory inputs. Healthy young subjects with 22 accelerometers attached to their backs were evaluated for head–trunk vibration during quiet standing under two conditions: one with open eyes and one with closed eyes. The synchronization of the acceleration and the instantaneous phase was then calculated. The results showed that the synchronization of acceleration and instantaneous phase varied depending on the visual condition, and there were some continuous coherent patterns in each condition. Findings were that the structural redundancy of the head–trunk, which is multi-segmental and has a high mass ratio in the whole body, must be adjusted adaptively according to the conditions to stabilize upright standing in human-specific bipeds.

Malnutrition prevails among patients with heart failure (HF), increasing the likelihood of functional decline. We assessed the predictive value of the Hemoglobin-Geriatric Nutritional Risk Index (H-GNRI)—combining hemoglobin and the Geriatric Nutritional Risk Index (GNRI)—on prognosis in older patients with HF. We used the JMDC multicenter database to examine the potential associations between malnutrition risk and other outcome measures. The patients were categorized as low- (H-GNRI score = 0), intermediate- (H-GNRI score = 1), or high-risk (H-GNRI score = 2) based on their H-GNRI scores. The primary outcome measure was the Barthel Index (BI) gain; the secondary outcomes included the BI at discharge, the BI efficiency, length of hospital stay, in-hospital mortality, discharge to home or a nursing home, and hospitalization-associated disability. We analyzed 3532 patients, with 244 being low-risk, 952 being intermediate-risk, and 2336 being high-risk patients. The high-risk group of patients had significantly lower BI values at discharge, lower BI gains, reduced BI efficiency values, and prolonged hospital stays compared to those in the low-risk group. The high-risk patients also had higher in-hospital mortality rates, lower rates of discharge to home or a nursing home, and greater incidences of a hospitalization-associated disability in comparison to the low-risk group. The H-GNRI may serve as a valuable tool for determining prognoses for patients with HF.

Abstract Background Progression of renal anemia has been shown to be associated with advanced renal tubulointerstitial lesions. This retrospective study investigated the impact of lower hemoglobin (Hb) levels and renal interstitial fibrosis and tubular atrophy (IFTA) on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy. Methods A total of 233 patients were enrolled. The severity of IFTA was scored according to the classification by the Renal Pathology Society. Patients were stratified according to baseline Hb tertiles by IFTA status. The outcomes were the first occurrence of renal events (requirement for dialysis or 50 % decline in estimated glomerular filtration rate from baseline) and all-cause mortality. Results At baseline, 151 patients had severe IFTA. There were no patients who have been received erythropoiesis-stimulating agents at the time of renal biopsy. The severity of IFTA was the independent pathological factor of lower Hb levels. During the mean follow-up period of 8.6 years (maximum, 32.4 years), 119 renal events and 42 deaths were observed. Compared with the combined influence of the highest tertile of Hb and mild IFTA, the risks of renal events were higher for the middle tertile and for the lowest tertile of Hb in severe IFTA, whereas the risk of renal events was higher for the lowest tertile of Hb in mild IFTA. The risk of mortality was higher for the lowest tertile of Hb only in severe IFTA. There were significant interactions of tertile of Hb and IFTA in renal events and mortality. Conclusions Impacts of lower Hb levels on long-term outcomes of diabetic nephropathy were greater in severe IFTA than in mild IFTA.

Abstract Introduction The number of patients with end stage kidney disease (ESKD) are increasing world-side. While interstitial fibrosis (IF) is a common step for the progression to ESKD, therapeutic options for IF is still limited in clinical settings. We have reported that bone marrow-derived fibrotic cell, fibrocyte, is involved in the pathogenesis of kidney fibrosis. Also recent studies revealed that erythropoietin has protective effect on kidney diseases. However, it is unknown whether erythropoietin (EPO) inhibits fibrosis in progressive kidney injury. Therefore, we explored the impacts of EPO on kidney fibrosis with focusing on fibrocyte. Method Fibrocyte was differentiated from peripheral mononuclear cells of healthy donor. Fibrocyte was stimulated with transforming growth factor beta (TGF)-β with/without EPO treatment. Moreover, the therapeutic effect of EPO was evaluated in murine unilateral ureteral obstruction (UUO) model. Result TGF-β stimulation increased the expression of COL1 mRNA in fibrocyte. EPO signal reduced the expression of COL1 mRNA in dose dependent manner. EPO reduced mitochondrial oxidative stress and ameliorated mitochondrial membrane depolarization induced by TGF-β stimulation. Moreover, EPO reduced the mRNA expression of mitochondria related molecules, TRAF6, in fibrocyte. In addition, the count of CD45+/αSMA + double-positive fibrocyte was decreased in the EPO-administered UUO kidneys. Conclusion EPO signals function to prevent kidney fibrosis, particularly in fibrocyte. Regulating the renal accumulation of fibrocyte is a part of the anti-fibrotic functions of EPO.

Abstract Carnitine/organic cation transporter 1 (OCTN1) is the only known uptake transporter for ergothioneine which is a food-derived strong antioxidant amino acid that is absorbed by OCTN1. We previously reported the roles of OCTN1/ergothioneine in the progression of kidney fibrosis in ischemic kidney disease. In this study, we evaluated the roles of OCTN1 in the progression of diabetic kidney disease. A diabetic kidney disease model was induced in octn1 knockout and wild-type mice by streptozotocin (STZ). Oxidative stress, represented by urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), were higher in the octn1 knockout mice. Azan- and Sirius red-positive areas increased significantly in the octn1 knockout mice. Gene expression was evaluated by cluster analysis, and shown to be different in the octn1 knockout mice compared with the wild-type mice. In a pathway analysis, the pathway associated with the cytoskeleton and cell adhesion increased. In accordance with interstitial fibrosis in octn1 knockout mice, gene expression of moesin in the injured kidney, known as an associated protein of cytoskeleton and cell membranes, was doubled 28 weeks after STZ injection. In addition, the moesin protein was expressed in a part of α-SMA-positive renal tubular epithelial cells. These findings were confirmed by cultured murine proximal tubular epithelial cells: The expression of moesin was induced under oxidative stress with hydrogen peroxide. These data indicate that OCTN1 would play some roles in progression of interstitial fibrosis under oxidative stress via moesin expression in diabetic kidney disease.

Abstract Background Annual decline in kidney function is a widely applied surrogate outcome of renal failure. It is important to understand the relationships between known risk factors and the annual decline in estimated glomerular filtration rate (eGFR) according to baseline age; however, these remain unclear. Methods A community-based retrospective cohort study of adults who underwent annual medical examinations between 1999 and 2013 was conducted. The participants were stratified into different age groups (40–49, 50–59, 60–69, 70–79, and ≥ 80 years) to assess the risk for loss of kidney function. A mixed-effects model was used to estimate the association between risk factors and annual changes in eGFR. Results In total, 51,938 participants were included in the analysis. The age group of ≥80 years included 8127 individuals. The mean annual change in eGFR was − 0.39 (95% confidence interval: − 0.41 to − 0.37) mL/min/1.73 m2 per year. Older age was related to faster loss of kidney function. In the older age group, higher systolic blood pressure, proteinuria, and current smoking were related to faster loss of kidney function (p trend

Abstract Background Minimal change disease (MCD) is one of the causes of idiopathic nephrotic syndrome in adults. The pathogenesis of proteinuria in MCD has not been fully understood. Recently, it has been reported that the receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL) may contribute to the podocyte biology in kidney diseases. Denosumab is a human anti-RANKL monoclonal antibody used to treat osteoporosis. Here we report a case of MCD after denosumab administration. Case presentation A 59-year-old male without any episodes of proteinuria was given denosumab to treat osteoporosis. Two weeks after its administration, he noticed a foamy urine and bilateral pretibial edema. Laboratory tests revealed that he had severe proteinuria (15g/g Cr), hypoproteinemia (4.0g/dL), and hypoalbuminemia (1.5g/dL). Based on the results, he was diagnosed with nephrotic syndrome. The proteinuria selectivity index was 0.05, indicating selective proteinuria. Renal biopsy showed minor glomerular abnormality with less tubulointerstitial damage, and electron microscopy showed extensive foot process effacement, indicating MCD. With all these results, glucocorticoid therapy of 50mg/day prednisolone was started. After 4weeks of treatment, the urinary protein level remains high (3.1g/g Cr). Prednisolone therapy was continued, and the levels of proteinuria decreased gradually to the range of partial remission (1.2g/g Cr) with another 7weeks of prednisolone treatment, but complete remission was not achieved. Conclusions This might be a case wherein RANKL inhibition is associated with the pathogenesis of MCD. Further studies will be needed to elucidate the causal relationship of RANK-RANKL signaling to the pathogenesis of MCD.

Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) causes hospital- and community-acquired infections. It is not clear whether genetic characteristics of the bacteria contribute to disease pathogenesis in MRSA infection. We hypothesized that whole genome analysis of MRSA strains could reveal the key gene loci and/or the gene mutations that affect clinical manifestations of MRSA infection. Methods: Whole genome sequences (WGS) of MRSA of 154 strains were analyzed with respect to clinical manifestations and data. Further, we evaluated the association between clinical manifestations in MRSA infection and genomic information. Results: WGS revealed gene mutations that correlated with clinical manifestations of MRSA infection. Moreover, 12 mutations were selected as important mutations by Random Forest analysis. Cluster analysis revealed strains associated with a high frequency of bloodstream infection (BSI). Twenty seven out of 34 strains in this cluster caused BSI. These strains were all positive for collagen adhesion gene (cna) and have mutations in the locus, those were selected by Random Forest analysis. Univariate and multivariate analysis revealed that these gene mutations were the predictor for the incidence of BSI. Interestingly, mutant CNA protein showed lower attachment ability to collagen, suggesting that the mutant protein might contribute to the dissemination of bacteria. Conclusions: These findings suggest that the bacterial genotype affects the clinical characteristics of MRSA infection. Keywords: MRSA, Bloodstream infection, Cna, Whole genome sequencing

The full-length receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor. High-mobility group box 1 (HMGB1) is a RAGE ligand of damage-associated molecular patterns that elicits inflammatory reactions. The shedded isoform of RAGE and endogenous secretory RAGE (esRAGE), a splice variant, are soluble isoforms (sRAGE) that act as organ-protective decoys. However, the pathophysiologic roles of RAGE/sRAGE in acute kidney injury (AKI) remain unclear. We found that AKI was more severe, with enhanced renal tubular damage, macrophage infiltration, and fibrosis, in mice lacking both RAGE and sRAGE than in wild-type (WT) control mice. Using murine tubular epithelial cells (TECs), we demonstrated that hypoxia upregulated messenger RNA (mRNA) expression of HMGB1 and tumor necrosis factor α (TNF-α), whereas RAGE and esRAGE expressions were paradoxically decreased. Moreover, the addition of recombinant sRAGE canceled hypoxia-induced inflammation and promoted cell viability in cultured TECs. sRAGE administration prevented renal tubular damage in models of ischemia/reperfusion-induced AKI and of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. These results suggest that sRAGE is a novel therapeutic option for AKI.

Introduction Data on the association between longitudinal trajectory patterns of albuminuria and subsequent end-stage kidney disease (ESKD) and all-cause mortality in diabetic kidney disease (DKD) are sparse.Research design and methods Drawing on nationally representative data of 329 patients with biopsy-proven DKD and an estimated glomerular filtration rate above 30 mL/min/1.73 m2 at the time of biopsy, we used joint latent class mixed models to identify different 2-year trajectory patterns of urine albumin to creatinine ratio (UACR) and assessed subsequent rates of competing events: ESKD and all-cause death.Results A total of three trajectory groups of UACR were identified: ‘high-increasing’ group (n=254; 77.2%), ‘high-decreasing’ group (n=24; 7.3%), and ‘low-stable’ group (n=51; 15.5%). The ‘low-stable’ group had the most favorable risk profile, including the baseline UACR (median (IQR) UACR (mg/g creatinine): ‘low-stable’, 109 (50–138); ‘high-decreasing’, 906 (468–1740); ‘high-increasing’, 1380 (654–2502)), and had the least subsequent risk of ESKD and all-cause death among the groups. Although there were no differences in baseline characteristics between the ‘high-decreasing’ group and the ‘high-increasing’ group, the ‘high-decreasing’ group had better control over blood pressure, blood glucose, and total cholesterol levels during the first 2 years of follow-up, and the incidence rates of subsequent ESKD and all-cause death were lower in the ‘high-decreasing’ group compared with the ‘high-increasing’ group (incidence rate of ESKD (per 1000 person-years): 32.7 vs 77.4, p=0.014; incidence rate of all-cause death (per 1000 person-years): 0.0 vs 25.4, p=0.007).Conclusions Dynamic changes in albuminuria are associated with subsequent ESKD and all-cause mortality in DKD. Reduction in albuminuria by improving risk profile may decrease the risk of ESKD and all-cause death.

Introduction Changes in albuminuria or estimated glomerular filtration rate (eGFR) can be used as a surrogate endpoint of end-stage kidney disease (ESKD) in people with type 2 diabetes. We investigated whether the combined changes in albuminuria and eGFR are more strongly associated with future risk of ESKD.Research design and methods Using data from a multicenter observational cohort study of people with type 2 diabetes, we evaluated the association of percentage change in urine albumin to creatinine ratio (UACR) and/or annual change in eGFR over 2 years with subsequent ESKD risk.Results Among 1417 patients with repeated albuminuria and eGFR over 2 years, 129 (9.1%) developed ESKD. Patients with >30% UACR decline had lower ESKD risk (HR 0.47; 95% CI 0.29 to 0.77), whereas those with >30% UACR increase had higher ESKD risk (HR 2.31; 95% CI 1.52 to 3.51), compared with those with minor UACR change. Patients with greater eGFR decline had an increased ESKD risk than those with minor eGFR change (a decline of 5 and 2.5–5 mL/min/1.73 m2/year, respectively. When the combined changes in UACR and eGFR were used, the highest ESKD risk (HR 5.60; 95% CI 2.08 to 15.09) was observed among patients with >30% UACR increase and an eGFR decline of >5 mL/min/1.73 m2/year compared with those with a minor change in UACR and eGFR.Conclusions Combined changes in albuminuria and eGFR over 2 years were strongly associated with future risk of kidney failure in patients with type 2 diabetes.

Abstract Aims/Introduction The present retrospective study investigated the impact of renal arteriosclerosis (AS) and hypertension (HT) on long‐term renal and cardiovascular outcomes in Japanese type 2 diabetes patients with biopsy‐proven diabetic nephropathy. Materials and Methods A total of 185 patients were enrolled. Patients were divided into four groups stratified by renal AS status and the presence of HT. The outcomes for this study were the first occurrence of renal events (a need for dialysis or a 30% decline in estimated glomerular filtration rate from baseline) and cardiovascular events (cardiovascular death, non‐fatal myocardial infarction, coronary intervention or non‐fatal stroke). Results The proportion of renal AS scores ≥1 was 88.3% among patients with normal‐range blood pressure (BP) and 95.4% among patients with HT. During a mean follow‐up period of 7.6 years, 129 episodes of renal composite events and 55 episodes of cardiovascular events were observed. Compared with patients with no renal AS and normal‐range BP, a renal AS score ≥1 increased the risk of renal composite events with a multivariable‐adjusted hazard ratio of 3.21 (95% confidence interval [95% CI] 1.27–8.14) in patients with normal‐range BP and 4.99 (95% CI 1.98–12.54) in patients with HT, whereas renal AS score ≥1 increased the risk of cardiovascular events with a multivariable‐adjusted hazard ratio of 6.06 (95% CI 1.24–29.61) in patients with normal‐range BP and 10.02 (95% CI 1.92–52.39) in patients with HT. Conclusions Renal AS was associated with increasing risks for renal composite events and cardiovascular events in both normal‐range BP and HT. The risks of renal composite events and cardiovascular events were the highest in both renal AS and HT.

Diabetes is a major cause of kidney disease. Here Kikuchi et al. show that phenol sulfate, a gut microbiota-derived metabolite, is increased in diabetic kidney disease and contributes to the pathology by promoting kidney injury, suggesting phenyl sulfate could be used a marker and therapeutic target for the treatment of diabetic kidney disease.

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 p = 0.041). Thus, anti-EPOR antibody positivity was associated with left ventricular dysfunction in patients undergoing HD.

Yokukansankachimpihange is a Japanese herbal medicine reported to benefit anxiety and sleep disorders, and it has recently been introduced to treat behavioral and psychological symptoms of dementia. There are no multicenter studies of its effectiveness regarding dementia in Japan, and this study's main objective was to clarify the effects of Yokukansankachimpihange on behavioral and psychological symptoms of dementia in a sample of patients from multiple healthcare centers. Nine facilities affiliated with Osaka Association of Psychiatric Clinics participated in November 2013 through April 2015 and provided 32 Alzheimer's disease patients to whom Yokukansankachimpihange was orally administered for 8 weeks. During the study, the patients continued their regular medication regimens. Behavioral and psychological symptoms of dementia (Behavioral Pathology in Alzheimer's Disease Rating Scale [Behave-AD]), core symptoms [Mini-Mental State Examination (MMSE)], activities of daily living [Nishimura Activity of Daily Living Scale (N-ADL)], and gastrointestinal symptoms (nausea/vomiting, loss of appetite, gastric discomfort, constipation, and diarrhea) were measured at baseline, after 4 weeks of treatment and after 8 weeks of treatment. Yokukansankachimpihange was orally administered at a dosage of 7.5 g twice daily before or between meals for 8 weeks. The Behave-AD mean score significantly improved after 8 weeks of treatment. There were no significant changes in MMSE, N-ADL, or gastrointestinal symptoms; however, decreased gastrointestinal scores were observed after 8 weeks. There were no side effects related to Yokukansankachinpihange. Pharmaceutical treatments are important for treating behavioral and psychological symptoms of dementia, and this study confirmed Yokukansankachimpihange's efficacy for treating Alzheimer's disease. Because the aggressiveness and sleep disorder components of the Behave-AD construct were the symptoms most improved and those symptoms are known to significantly burden dementia patients' caregivers, Yokukansankachimpihange's efficacy might indirectly relieve these caregivers' burden of care.

Summary 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.

ObjectiveGlomerular filtration rate (GFR) decreases without or prior to the development of albuminuria in many patients with diabetes. Therefore, albuminuria and/or a low GFR in patients with diabetes is referred to as diabetic kidney disease (DKD). A certain proportion of patients with diabetes show a rapid progressive decline in renal function in a unidirectional manner and are termed early decliners. This study aimed to elucidate the prevalence of DKD and early decliners and clarify their risk factors.Research design and methodsThis combination cross-sectional and cohort study included 2385 patients with diabetes from 15 hospitals. We defined DKD as a urinary albumin to creatinine ratio (ACR) ≥30 mg/gCr and/or estimated glomerular filtration rate (eGFR)

Introduction The speed of declining kidney function differs among patients with diabetic nephropathy. This study was undertaken to clarify clinical and pathological features that affect the speed of declining kidney function in patients with diabetic nephropathy.Research design and methods This study was design as multicenter retrospective study. The subjects (377 patients with diabetic nephropathy diagnosed by kidney biopsy at 13 centers in Japan) were classified into three groups based on the estimated glomerular filtration rate (eGFR) declining speed. The eGFR increasing group, the control group, and the eGFR declining group were divided at 0 and 5 mL/min/1.73 m2/year, respectively. Characteristics of clinicopathological findings of declining kidney function were evaluated.Results The mean observation period of this study was 6.9 years. The control group, the eGFR increasing group, and the eGFR declining group included 81, 66, and 230 patients, respectively. The incidences of composite kidney events represented by 100 persons/year were 25.8 in the eGFR declining group and 2.0 in the eGFR increasing group. After adjustment for age, sex, systolic blood pressure, hemoglobin, and urinary albumin levels, three clinicopathological findings (urinary albumin levels, presence of nodular lesion, and mesangiolysis) were risk factors for inclusion in the eGFR declining group (the ORs were 1.49, 2.18, and 2.08, respectively). In contrast, the presence of subendothelial space widening and polar vasculosis were characteristic findings for inclusion in the eGFR increasing group (the ORs were 0.53 and 0.41, respectively).Conclusions As well as urinary albumin elevation, nodular lesion and mesangiolysis were characteristic pathological features of patients with fast declining kidney function.

We examined the impact of autoantibodies on the erythropoietin receptor (EPOR) in type 2 diabetic patients with chronic kidney disease (CKD). Methods: A total of 112 Japanese patients with type 2 diabetes who had CKD were enrolled in this study and followed for a mean of 45 months. Sera from these patients were screened for anti-EPOR antibodies using enzyme-linked immunosorbent assays. Results: Anti-EPOR antibodies were detected in 26 patients (23%). Anti-EPOR antibodies were associated with low hemoglobin concentrations and decreased renal function. In patients with biopsy-proven diabetic nephropathy, anti-EPOR antibodies were associated with increased levels of interstitial inflammation. A decrease in renal function was observed more frequently in patients with antibodies than in those without antibodies, and the presence of the antibodies together with well-known clinical parameters, including proteinuria and low glomerular filtration rate, was a significant risk factor for end-stage renal disease. In human tubular epithelial HK-2 cells, IgG fractions containing anti-EPOR antibodies upregulated the expression of monocyte chemoattractant protein-1 mRNA under a high concentration of glucose. Conclusion: Anti-EPOR antibodies might be involved in the progression of renal lesions and in the impaired erythropoiesis in type 2 diabetic patients with CKD. Furthermore, the presence of anti-EPOR antibodies may be an additional predictor for end-stage renal disease in type 2 diabetes.

Abstract Peritoneal fibrosis (PF) is a serious complication in various clinical settings, but the mechanisms driving it remain to be fully determined. Connective tissue growth factor (CTGF) is known to regulate fibroblast activities. We therefore examined if CTGF inhibition has anti-fibrotic effects in PF. PF was induced by repetitive intraperitoneal injections of chlorhexidine gluconate (CG) in mice with type I pro-collagen promoter-driven green fluorescent protein (GFP) expression to identify fibroblasts. FG-3019, an anti-CTGF monoclonal antibody, was used to inhibit CTGF. CG-induced PF was significantly attenuated in FG-3019-treated mice. CG challenges induced marked accumulations of proliferating fibroblasts and of myofibroblasts, which were both reduced by FG-3019. Levels of peritoneal CTGF expression were increased by CG challenges, and suppressed in FG-3019-treated mice. FG-3019 treatment also reduced the number of CD31+ vessels and VEGF-A-positive cells in fibrotic peritoneum. In vitro studies using NIH 3T3 fibroblasts and peritoneal mesothelial cells (PMCs) showed that CTGF blockade suppressed TGF-β1-induced fibroblast proliferation and myofibroblast differentiation, PMC mesothelial-to-mesenchymal transition, and VEGF-A production. These findings suggest that the inhibition of CTGF by FG-3019 might be a novel treatment for PF through the regulation of fibroblast and myofibroblast accumulation and angiogenesis.

PURPOSE:To evaluate real-world evidence for intraocular pressure (IOP) elevation after subtenon triamcinolone acetonide injection (STTA) in 1252 Japanese patients (1406 eyes) in the Japan Clinical REtina STudy group (J-CREST). METHODS:This was a multicentre retrospective study of the medical records of 1252 patients (676 men (758 eyes); mean age: 63.8 ± 12.9 years) who received STTA in participating centres between April 2013 and July 2017. RESULTS:IOP elevation was observed in 206 eyes (14.7%) and IOP increase ≥ 6 mmHg was found in 328 eyes (23.3%). In total, 106 eyes (7.5%) needed medication and two eyes (0.14%) needed surgical procedures. Younger age, higher baseline IOP, and steroid dose were risk factors associated with IOP elevation. Risk factors associated with IOP increase ≥ 6 mmHg were younger age, lower baseline IOP, steroid dose, and higher incidences of diabetic macular oedema (DME) and uveitis. In contrast, with steroid dose fixed at 20 mg, a lower incidence of DME was a risk factor for increased IOP, suggesting that STTA had dose-dependent effects on IOP increase, especially in patients with DME. CONCLUSION:Our real-world evidence from a large sample of Japanese patients who received STTA showed that the incidence of IOP elevation after STTA was 14.7%, and was associated with younger age, higher baseline IOP, and steroid dose. Thus, IOP should be monitored, especially in patients with younger age, higher baseline IOP, and higher incidences of DME and uveitis.

The aim of this study was to clarify whether the physiological fatigue status of elite speed skaters is influenced by the approximately five-month international competition season by comparing morning heart rate variability (HRV) at the beginning of the competition season (Japan Single Distances Championships: JSDC) with that at the end of the competition season (World Single Distances Championships: WSDC). Five international-class speed skaters participated in the study. HRV indices and subjective fatigue were measured each morning of the four days prior to the first races of the JSDC and WSDC in the 2007/2008 season. The parasympathetic HRV indices: root mean square of the successive R-R interval differences (RMSSD) (JSDC, 61.0 ms; WSDC, 42.1 ms; p < 0.05), high-frequency component power (HF) (JSDC, 1393 ms2; WSDC, 443 ms2; p < 0.05), and normalized unit of HF (HFnu) (JSDC, 53.2%; WSDC, 25.5%; p < 0.05) were lower for the WSDC than for the JSDC. The decrease in these indices may reflect the skaters’ accumulated fatigue during the course of the competition season. Morning measurements of HRV may thus be an efficient way for elite speed skaters and coaches to objectively monitor physiological fatigue throughout the competition season.

This study aimed to clarify whether changes in the fatigue status of elite athletes during a precompetition period could be evaluated using morning heart rate variability (HRV) indices. Eight Japanese National Badminton Team players (age, 23.0 ± 2.8 years) participated in this study. HRV and subjective fatigue were measured during the first (days 1–4: Phase 1) and the second half (days 5–8: Phase 2) of an 8-day national team training camp. The global and parasympathetic HRV indices were as follows: standard deviation of all R-R intervals (SDNN) (Phase 1, 87.5 ms; Phase 2, 104.3 ms; p < 0.05), root mean square of the successive R-R interval differences (RMSSD) (Phase 1, 66.6 ms; Phase 2, 103.6 ms; p < 0.05), and high-frequency component power (HF) (Phase 1, 1412.0 ms2; Phase 2, 3318.5 ms2; p < 0.05). All the aforementioned indices increased significantly from Phase 1 to Phase 2. Significant correlations were observed between the change in subjective fatigue and changes in SDNN, RMSSD, and HF (ρ = −0.80, p = 0.017; ρ = −0.77, p = 0.027; and ρ = −0.80, p = 0.017, respectively). Measuring morning HRV indices may be effective for objectively evaluating changes in the fatigue status of elite athletes during a precompetition period.

The relationship between dietary habits and development of chronic kidney disease (CKD) is unclear. This retrospective cohort study was conducted to examine the association between unhealthy dietary habits and proteinuria onset, a key prognostic factor of CKD, among a Japanese general population aged ≥40 years. The risks of proteinuria onset were estimated based on the status of baseline unhealthy dietary habits (quick eating, late dinner, late evening snack, and skipping breakfast) compared with the status without these habits. A total of 26,764 subjects were included, with a mean follow-up period of 3.4 years. The most frequent unhealthy dietary habit was quick eating (29%), followed by late dinner (19%), late evening snack (16%), and skipping breakfast (9%). During the follow-up period, 10.6% of participants developed proteinuria. Late dinner and skipping breakfast showed an increased adjusted risk of proteinuria onset (hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.02 to 1.22, and HR 1.15, 95% CI 1.01 to 1.31, respectively). Unhealthy dietary habits were not associated with changes in body mass index or waist-to-height ratio during the follow-up period. Our results suggest that late dinner and skipping breakfast are associated with higher risks for proteinuria onset.