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Patient registries have great potential for providing data that describe the natural history, epidemiology, disease burden, treatments, and outcomes. The Japan Renal Biopsy Registry (J-RBR) was started in 2007 and the Japan Kidney Disease Registry (J-KDR) was then started in 2009 by the Japanese Society of Nephrology. Analysis of the J-RBR/J-KDR identified clinical factors associated with the different diagnosis of renal disease in patients with diabetes. Furthermore, the Japan Diabetic Nephropathy Cohort Study (JDNCS), a nationwide observational study for adult Japanese patients with type 2 diabetes and clinically suspected diabetic nephropathy, was initiated in 2009. Analysis of the JDNCS demonstrated the association between estimated glomerular filtration rate (eGFR) and albuminuria at baseline or during follow-up and outcomes.

Introduction Although therapeutic agents for methicillin-resistant Staphylococcus aureus (MRSA) are clinically available, MRSA infection is still a life-threatening disease. Bacterial attachment and biofilm formation contribute significantly to the initiation of MRSA infection. Controlling MRSA’s attachment and biofilm formation might reduce the frequency of MRSA infection. According to recent data, some amino acids can reduce MRSA’s attachment on plates; however, their precise inhibitory mechanisms remain unclear. Therefore, we explored the effect of the amino acids on bacterial adhesion and biofilm formation in vitro and in vivo MRSA infection models. Methods We tested the inhibitory effect of amino acids on MRSA and Escherichia coli (E. coli) in the attachment assay. Moreover, we evaluated the therapeutic potential of amino acids on the in vivo catheter infection model. Results Among the amino acids, D-Serine (D-Ser) was found to reduce MRSA’s ability to attach on plate assay. The proliferation of MRSA was not affected by the addition of D-Ser; thus, D-Ser likely only played a role in preventing attachment and biofilm formation. Then, we analyzed the expression of genes related to attachment and biofilm formation. D-Ser was found to reduce the expressions of AgrA, SarS, IcaA, DltD, and SdrD. Moreover, the polyvinyl chloride catheters treated with D-Ser had fewer MRSA colonies. D-Ser treatment also reduced the severity of infection in the catheter-induced peritonitis model. Moreover, D-Ser reduced the attachment ability of E. coli. Conclusion D-Ser inhibits the attachment and biofilm formation of MRSA by reducing the expression of the related genes. Also, the administration of D-Ser reduces the severity of catheter infection in the mouse model. Therefore, D-Ser may be a promising therapeutic option for MRSA as well as E. coli infection.

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 p trend 0.47 and 0.17, respectively). Conclusions Higher systolic blood pressure, proteinuria, and smoking were related to faster loss of kidney function, and a greater effect size was observed in the older participants. More risk assessments for older people are required for personalized care.

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 &plusmn, 2.8 years) participated in this study. HRV and subjective fatigue were measured during the first (days 1&ndash, 4: Phase 1) and the second half (days 5&ndash, 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 &lt, 0.05), root mean square of the successive R-R interval differences (RMSSD) (Phase 1, 66.6 ms, Phase 2, 103.6 ms, 0.05), and high-frequency component power (HF) (Phase 1, 1412.0 ms2, Phase 2, 3318.5 ms2, 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 (&rho, = &minus, 0.80, p = 0.017, &rho, 0.77, p = 0.027, and &rho, 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.

Preclinical left ventricular diastolic dysfunction (LVDD) is a high-risk state for heart failure. Kidney dysfunction is a known risk factor for heart failure, but its association with asymptomatic LVDD is not well-known. A hospital-based retrospective cohort study was conducted on patients who underwent echocardiogram between 2006 and 2016 to assess the association between baseline kidney function and LVDD on echocardiogram. E/e′ ratio was defined as the ratio of peak velocity of early diastolic left ventricular inflow (E) to mitral annular velocity (e′). The primary outcome was time to development of LVDD, which was defined as E/e′ ratio > 14. The changes in the E/e′ ratio and other echocardiographic parameters were assessed using a mixed effects model. Among 1167 patients, the mean age was 61 years, and the mean baseline E/e′ ratio and ejection fraction were 9.6 and 69%, respectively. During a median follow-up of 3.2 years, 231 (19.8%) people developed LVDD. According to eGFR (mL/min/1.73 m2), the risk for LVDD based on hazard ratio [95% confidence interval (95% CI)] was 1.20 (0.82, 1.75) for 60 to

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 &ge, 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.

Recent studies revealed that lysophospholipids (LPLs) and related molecules, such as autotaxin (ATX) and phosphatidylserine-specific phospholipase AIn this retrospective cohort study, serum samples were collected from 39 patients with LN and 37 patients with other glomerular diseases. The serum levels of ATX and PS-PLAThe serum levels of ATX and PS-PLAAlthough the serum levels of ATX and PS-PLA

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., 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. Changes in albuminuria 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.

The purpose of this study was to clarify whether there have been any specific changes in the characteristics of the world&rsquo, s top-level women&rsquo, s singles badminton matches compared to men&rsquo, s singles matches after the current badminton scoring system was implemented in 2006. We compared the characteristics of the matches between the Super Series tournaments in 2007 and 2017. Match duration increased as the rally and rest times increased in both men&rsquo, s and women&rsquo, s singles matches. Specifically, in women&rsquo, s singles, it was suggested that a further increase in physical demands because of the increased number of shots per second may have resulted in longer rest time in proportion to rally time. Moreover, increases in match duration (final eight, 53.3 &plusmn, 6.6 min, early rounds, 42.1 &plusmn, 3.6 min, P &lt, 0.05) and number of shots per rally (final eight, 10.4 &plusmn, 1.2, early rounds, 8.7 &plusmn, 1.1, 0.05) in women&rsquo, s singles were more prominent in the final eight rounds (quarterfinals, semifinals, and finals) than in the early rounds (rounds 1 and 2). The recent changes in characteristics of the world&rsquo, s top-level badminton matches may account for the increased acute injuries that are frequently observed in elite women&rsquo, s singles players. Thus, appropriate training programs are crucial to effectively improve performance and prevent injuries among elite badminton players.

Frailty may predict adverse events in patients with hip fractures. This study aimed to investigate the association between frailty and adverse events in patients with hip fractures after surgery using information from Japanese health insurance.This retrospective cohort study included patients with hip fractures aged ≥ 65 years using a nationwide database in Japan. We examined the relationship of the frailty risk, which was defined using the Hospital Frailty Risk Score (HFRS), with in-hospital mortality, complications such as delirium and pneumonia, and functional outcomes. We used descriptive analysis, logistic regression, and linear regression analysis to estimate the association between the HFRS and outcomes in patients with hip fracture.We analysed data from 36,192 patients with hip fractures after surgery (mean age: 83.6 ± 6.7 years, female: 79.5%). The proportions of low, intermediate, and high risk of frailty were 68.4%, 28.1%, and 3.5%, respectively. The frailty risk was independently associated with in-hospital mortality (intermediate risk: odds ratio [OR] 1.385, P0.001; high risk: OR 1.572; P0.001) and the occurrence of complications. Furthermore, each frailty risk was negatively associated with the Barthel Index score at discharge (intermediate risk: coefficient -11.919, P0.001; high risk: coefficient -18.044; P0.001).The HFRS could predict adverse events, including in-hospital mortality, in Japanese older patients with hip fractures. This finding supports the validity of using the HFRS in clinical practice for patients with hip fractures.

Signs of aging in facial skin correlate with lifespan and chronic disease; however, the health of aging skin has not been extensively studied. In healthy young skin, the dermis forms a type III collagen-rich dermal papilla, where capillary vessels supply oxygen and nutrients to basal epidermal cells. Chicken eggshell membranes (ESMs) have been used as traditional medicines to promote skin wound healing in Asian countries for many years. Previously, we designed an experimental system in which human dermal fibroblasts (HDFs) were cultured on a dish with a solubilized ESM (S-ESM) bound to an artificial phosphorylcholine polymer; we found that genes that promoted the health of the papillary dermis, such as those encoding type III collagen, were induced in the S-ESM environment. The present study found that a gel with a ratio of 20% type III/80% type I collagen, similar to that of the baby skin, resulted in a higher elasticity than 100% type I collagen (p

Introduction There have been no studies directly comparing the effect of dipeptidyl peptidase-4 inhibitors with that of metformin on treatment-related quality of life (QOL) when used as first-line therapy in patients with type 2 diabetes mellitus (T2DM). Methods This study is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. Forty-four participants who failed to achieve target glycemic control with diet and exercise therapy were randomly allocated to receive linagliptin or metformin therapy. We compared treatment-related QOL among the two groups using the Oral Hypoglycemic Agent Questionnaire, version 2 (OHA-Q version 2) and the self-administered Diabetes Therapy-Related QOL (DTR-QOL) questionnaire. Results After randomization, 21 patients in the linagliptin group and 22 patients in the metformin treatment group were included in the full analysis set. Biochemical parameters, incidence of adverse effects, and rate of adherence to medication were comparable between the two groups. Over the 24-week treatment period, no significant differences in overall OHA-Q scores between the groups were observed, although the subscale 1 (treatment convenience) score was significantly higher in the linagliptin group than in the metformin group. The overall DTR-QOL score did not differ between the two groups; however, the DTR-QOL scores significantly improved after 24 weeks of linagliptin treatment, but not after metformin treatment. Conclusion We did not find significantly better treatment-related QOL with linagliptin among Japanese patients with T2DM. In terms of treatment convenience, our data showed that linagliptin was superior to metformin. Funding This study was financially supported by Nippon Boehringer Ingelheim Co., Ltd. and Eli Lilly and Company. The journal’s article processing fees were covered by a research fund from Juntendo University. Clinical Trial Registration UMIN000022953. Electronic Supplementary Material The online version of this article (10.1007/s13300-018-0539-5) contains supplementary material, which is available to authorized users.

Objectives: To clarify the relationship between mobility disability at the time of discharge from the ICU and clinical factors evaluated at ICU admission in septic patients. Design: A single-center, retrospective, observational study. Setting: Ten-bed, the emergency and medical ICU. Patients: We analyzed the data of septic patients who were admitted to our ICU between September 2012 and September 2016 and received early rehabilitation. Interventions: None. Measurements and Main Results: The patients were categorized into two groups based on their scores on the ICU mobility scale at the time of discharge from the ICU: the mobility disability group (ICU mobility scale score < 9) and the no mobility disability group (ICU mobility scale score ≥ 9). Of the 110 eligible patients, 63 met the inclusion criteria; of these, 46 patients (73%) were classified into the mobility disability group, and 17 patients (27%) were classified into the no mobility disability group. The age (median, 72 vs 64 yr; p = 0.024), prevalence of patients with clinical frailty scale scores of greater than or equal to 5 (54% vs 12%; p = 0.003), Sequential Organ Failure Assessment score (median, 9.0 vs 6.0; p = 0.006) and rate of vasopressin use (26% vs 0%; p = 0.026) were significantly higher in the mobility disability group as compared with the no mobility disability group. Among the candidate variables for which values recorded before/at the time of ICU admission were available, the clinical frailty scale score was identified as the only independent, statistically significant predictor of mobility disability at ICU discharge (odds ratio, 7.77; 95% CI, 1.37–44.21; p = 0.021). The positive predictive value and negative predictive value of clinical frailty scale scores greater than or equal to 5 for mobility disability at ICU discharge were 92.6% and 41.7%, respectively. Conclusions: The clinical frailty scale score was associated with increased mobility disability at ICU discharge in septic patients receiving early rehabilitation.

Background Postoperative cognitive dysfunction (POCD) is a neurologic dysfunction that occurs after surgery. POCD persists for a long period, ranging from weeks to months, and affects a patient's quality of life. A 6-minute walk distance (6MWD) has been used to predict postoperative complications after several operations. The present study investigated whether there was an independent association of a low preoperative 6MWD with POCD in patients who underwent cardiac operations. Methods The study included 181 patients who underwent a cardiac operation. The 6MWD was performed prospectively on admission for the operation. POCD was defined as a decrease of 2 points or more in a patient's Mini-Mental State Examination score. POCD developed in 51 (28%) of these patients. Patients were categorized into a POCD or a non-POCD group, and the perioperative variables were compared between the groups. Multivariable logistic regression analysis was performed to identify risk factors for the development of POCD. Results The patients were a mean age of 71.4 years. The POCD group showed a significantly lower 6MWD (median, 400 m) than the non-POCD group (median, 450 m). The 6MWD, intensive care unit length of stay, age, and Mini-Mental State Examination score were identified as independent risk factors for POCD by multivariable analysis. The odds ratio for each increase of 50 m in the 6MWD was 0.807 for POCD. Conclusions The 6MWD is useful in identifying patients with a higher chance of developing POCD after a cardiac operation.

Diabetic kidney disease is the main cause of end-stage kidney disease. However, the clinical manifestations of diabetic kidney disease are diverse. Therefore, the clinical classification of diabetic kidney disease is clinically important and valuable. In Japan, two clinical staging systems divided by the estimated glomerular filtration rate (eGFR) and albuminuria can be used for diabetic kidney disease: the chronic kidney disease (CKD) risk classification and the Japanese classification of diabetic nephropathy. The Japanese classification of diabetic nephropathy and the CKD risk classification are similar; however, these two classification systems show different frequencies of outcomes. For example, the frequency of the kidney outcomes in stage 4 of the Japanese classification of diabetic nephropathy was found to be higher than that in the red stage of the CKD risk classification (composite kidney events: stage 4=32.0/100 person-years, red =14.5/100 person-years). However, there were no marked differences in the speed or rate of decline in the kidney function (speed: stage 4=6.8 mL/min/1.73 m2/year, red =5.8 mL/min/1.73 m2/year; rate: stage 4=38.8%/year, red =34.3%/year) or in the pathological changes between the two classifications. These data indicate that each stage of these clinical classification systems has characteristic clinical and pathological features. Therefore, it is important to understand each characteristic feature and use each classification system appropriately.

Mortality from infections has been reported to be higher in hemodialysis (HD) patients. Although dysfunction of neutrophils against bacterial infection was reported in HD patients, the precise mechanism remains to be clarified. We therefore examined the impacts of neutrophil inflammatory signaling on bactericidal activity in HD patients. Comprehensive analyses of intracellular signalings were performed in whole blood of HD patients and control using a microarray system. To confirm the contribution of the signaling to bactericidal activity in neutrophils, we examined the phosphorylation, bacterial killing function, reactive oxygen species (ROS) production, and myeloperoxidase (MPO) release in neutrophils against Staphylococcus aureus. RNA microarray analysis showed the suppression of p38 mitogen activated protein kinase (MAPK) signaling in HD patients. Neutrophils in HD patients showed the impairment of bactericidal activity against S. aureus compared to healthy subjects. Phosphorylation rate of p38MAPK of neutrophils in response to S. aureus was lower in HD patients than healthy subjects. The levels of ROS produced by neutrophils after co-culture with S. aureus were lower in HD patients, on the other hand, there was no difference of MPO release between HD patients and healthy subjects. A selective pharmacological inhibitor of p38MAPK suppressed bacterial killing function as well as ROS production in neutrophils of healthy subjects. Impairment of p38MAPK signaling pathway might contribute to the suppression of neutrophil bactericidal activity in HD patients through less production of ROS.

金沢大学医薬保健研究域医学系, Introduction: 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. © 2017 International Society of Nephrology, Embargo Period 12 months

The aim of this study was to determine the prevalence and progression of diabetic retinopathy (DR) with hyperglycemic disorders during pregnancy (HDPs) in Japan between 2013 and 2018 using two cohorts. The patients with HDPs were classified as those with pre-existing DM (pexD), gestational DM (GDM), and overt DM (ODM). Cohort 1 was obtained from the health claims database whose diseases were classified by the International Classification of Diseases-10. Cohort 2 was derived from a retrospective, multicenter analysis of the medical records of 225 patients from 10 ophthalmological institutions. In Cohort 1, there were 5268 patients with an HDP prevalence of 8.4%. Among them, 73 of 1139 patients had pexD (6.4%) and 61 of 4129 patients with GDM (1.5%) had DR; the overall prevalence of DR was 2.5%. In Cohort 2, 36 of 225 patients (16.0%) had DR, and 149 patients were followed at the early and late stages of pregnancy. Moreover, 10 of the 102 patients with pexD (9.8%) and two of five patients with ODM (40.0%) had a progression of DR. In conclusion, the prevalence and progression of DR in patients with pexD is lower than previously reported. More attention should be given to pexD and ODM.

Background Two randomized, double-blind, placebo-controlled trials (EPPIC-1 and EPPIC-2) investigated the efficacy and safety of AST-120, an oral spherical carbon adsorbent, in adults with chronic kidney disease (CKD). While the benefit of adding AST-120 to standard therapy was not supported by these trials, we performed a post hoc analysis to focus on CKD progression and to determine the risk factors for the primary endpoint in the EPPIC trial population. Methods In the EPPIC trials, patients were randomly assigned 1:1 to treatment with AST-120 or placebo. The primary endpoint was a composite of dialysis initiation, kidney transplantation, or doubling of serum creatinine. The EPPIC trial pooled population was evaluated with the same statistical methods used for analysis of the primary and secondary efficacy endpoints. The trials were registered on ClinicalTrials.gov (NCT00500682 [EPPIC-1] and NCT00501046 [EPPIC-2]). Results An analysis of the placebo population suggested baseline urinary protein to urinary creatinine ratio (UP/UCr) ≥1.0 and hematuria were independent risk factors for event occurrence and eGFR lowering. Analysis of the high risk patients revealed a difference in the primary endpoint occurrence between treatment groups, if angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers were administered (hazard ratio 0.74, 95% confidence interval 0.56–0.96). Also, the eGFR changes from baseline in the AST-120 group were smaller than that in the placebo group (P = 0.035). Conclusions CKD progression may have an association with baseline UP/UCr and hematuria. Treatment with AST-120 may delay the time to the primary endpoint in patients with progressive CKD receiving standard therapy, thus warranting further investigation. Electronic supplementary material The online version of this article (doi:10.1007/s10157-017-1447-0) contains supplementary material, which is available to authorized users.

金沢大学医薬保健研究域医学系, Background. The clinical and pathologic manifestations of nephropathy due to type 2 diabetes are diverse, but large-scale pathologic studies with long-termobservations are limited. Methods. Kidney biopsies and clinical data of 600 patients with type 2 diabetes were collected retrospectively from 13 centres across Japan. Thirteen pathologic findings (nine glomerular lesions, two interstitial lesions and two vascular lesions) were clearly defined and scored. Results. During the observation period, there were 304 composite kidney events [dialysis, doubling of creatinine or reduction of estimated glomerular filtration rate (eGFR) by half], 31 instances of chronic kidney disease (CKD) G5D, 76 cardiovascular events and 73 deaths. The mean observation period was 72.4 months. The distribution of CKD heat map categories for the 600 patients was 103 green or yellow, 149 orange and 348 red. Even in the cases in the green and yellow category, diffuse lesions (81.6%), polar vasculosis (42.6%) and subendothelial space widening (35.1%) were commonly detected. Cox proportional hazard analysis revealed that the presence of nodular lesions [hazard ratio (HR) 21.1, 95% confidence interval (CI) 5.3-84.6], exudative lesions (HR 5.1, 95% CI 1.3-20.3) and mesangiolysis (HR 7.6, 95% CI 2.0-28.8) in cases in the green and yellow category were associated with significantly great impact on composite kidney events after adjustment for clinical risk factors. Conclusions. This nationwide study on kidney biopsy of 600 cases with type 2 diabetes revealed that pathologic findings (presence of nodular lesions, exudative lesions and mesangiolysis) were strong predictors of kidney events in low-risk patients. © The Author 2017., Embargo Period 12 months

Knowledgeof the choroidal structures in eyes with diabetes and diabetic retinopathy (DR) should provide information on the pathogenesis of DR. A prospective study was performed to determine the systemic and ocular factors that affect the choroidal structures in eyes with diabetes. Two-hundred consecutive diabetic subjects consisted of 160 treatment-naïve patients with different stages of DR and 40 patients with proliferative DR with prior panretinal photocoagulation (PRP). All underwent blood and urine tests and enhanced depth imaging optical coherence tomography (EDI-OCT). The cross-sectional EDI-OCT images of the subfoveal choroid were binarized to measure the total choroidal area (TCA), luminal area, and stromal area. Multivariate regression analyses were performed to determine the systemic and ocular factors that were significantly correlated with the choroidal structures. The subfoveal choroidal thickness, TCA, luminal area, and stromal area were larger at more advanced stage of DR, and smaller in eyes with PRP than those without (P P = 0.034, P = 0.025, respectively). The choroidal lumen and stroma may increase as the stages of DR progress and decrease after PRP. Albuminuria may be associated with the choroidal stromal edema.

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

A 60-year-old man was diagnosed with psoriasis 4 years ago. Treatment with adalimumab (a monoclonal anti-TNF-α antibody) became ineffective 1 year ago, and proteinuria and urinary occult blood were detected. Treatment with topical medicine, ultraviolet therapy, and etretinate resulted in remission of psoriasis, and proteinuria and hematuria also improved. For maintenance of remission, treatment with secukinumab (a human anti-interleukin-17A monoclonal antibody) was initiated. After the induction phase, treatment was changed from once a week to once every 4 weeks. After 5 months, he developed nephritis with kidney dysfunction, hematuria, and severe proteinuria (14 g/g Cr) accompanied by pitting edema. After admission, treatment with secukinumab was continued. Kidney biopsy revealed IgA nephropathy with fibrocellular crescents, and immunofluorescence analysis did not detect galactose-deficient IgA1. With these findings, he was diagnosed as secondary IgA nephropathy associated with psoriasis. Tonsillectomy followed by steroid pulse therapy prevented proteinuria and kidney function. In this case, treatment of refractory psoriasis with secukinumab and tonsillectomy was effective, leading to remission of relapsing secondary IgA nephropathy. Therefore, secukinumab might play an immunological role in the treatment of nephropathy.

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease., 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.

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.

Apoptosis inhibitor of macrophage (AIM) expressed on macrophages prolongs inflammation by protecting macrophages from apoptosis. Most circulating AIM co-exists with immunoglobulin M (IgM). AIM’s pathophysiological role in relation to IgM remains unclear. Here we evaluated the glomerular expression/deposition of AIM and IgM in the kidney using immunohistochemistry and its associations with clinical manifestations in 43 patients with biopsy-confirmed kidney diseases. Kidney biopsy tissue from all patients was immunostained for AIM and IgM. Staining patterns and percent stained areas within the glomeruli were determined. Cells expressing AIM were identified by co-staining with macrophage and endothelial cell surface markers. Correlations between staining results and clinical parameters were evaluated using univariate and multivariate analyses. AIM was deposited in various areas, such as mesangial and capillary area. A part of AIM expression was localized to CD68-positive macrophages in the glomerulus. Amount of glomerular expression was positively correlated with urinary protein in patients with severe proteinuria (urinary protein ≥0.5 g/day) and kidney dysfunction [estimated glomerular filtration ratio (eGFR)

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) ResultsOf our cohort, 52% had DKD. Above all, 12% with a low eGFR but no albuminuria had no traditional risk factors, such as elevated glycated hemoglobin, elevated blood pressure, or diabetic retinopathy in contrast to patients with albuminuria but normal eGFR. Additionally, 14% of our patients were early decliners. Older age, higher basal eGFR, higher ACR, and higher systolic blood pressure were significantly associated with early decliners.ConclusionsThe prevalence of DKD in this cohort was larger than ever reported. By testing eGFR yearly and identifying risk factors in the early phase of diabetes, we can identify patients at high risk of developing end-stage renal disease.

Resilience to stretch stress is an important characteristic that helps maintain cell adhesion and consequently, human health. This study aimed to elucidate the underlying mechanism of adaptation to stretch stress regulated by the molecular chaperone αB-crystallin. Three rat myoblast L6 cell lines, wild type (L6-WT), αB-crystallin knock down (L6-KD), and αB-crystallin overexpressing (L6-OE) cells were used. Muscle cells are less motile because they are specialized for contraction. Forced stretch stress was given to the three cell lines on a soft adhesive sheet, and we found that L6-OE cells showed the highest resilience to stretch stress and the least motility compared to other cell lines. Conversely, L6-KD cells showed the least resilience to stretch stress. Vinculin staining showed that total focal adhesion (FA) size and area of L6-OE cells were significantly larger than those of other cell types. Thus αB-crystallin in myoblast cells contributes the resilience of FA stability during stretch stress.

Gut microbiota–derived metabolites play important roles in health and disease. D–amino acids and their L-forms are metabolites of gut microbiota with distinct functions. In this study, we show the pathophysiologic role of D–amino acids in association with gut microbiota in humans and mice with acute kidney injury (AKI). In a mouse kidney ischemia/reperfusion model, the gut microbiota protected against tubular injury. AKI-induced gut dysbiosis contributed to the altered metabolism of D–amino acids. Among the D–amino acids, only D-serine was detectable in the kidney. In injured kidneys, the activity of D–amino acid oxidase was decreased. Conversely, the activity of serine racemase was increased. The oral administration of D-serine mitigated the kidney injury in B6 mice and D-serine–depleted mice. D-serine suppressed hypoxia-induced tubular damage and promoted posthypoxic tubular cell proliferation. Finally, the D-serine levels in circulation were significantly correlated with the decrease in kidney function in AKI patients. These results demonstrate the renoprotective effects of gut-derived D-serine in AKI, shed light on the interactions between the gut microbiota and the kidney in both health and AKI, and highlight D-serine as a potential new therapeutic target and biomarker for AKI.

OBJECTIVE Clinicopathological characteristics, renal prognosis, and mortality in patients with type 2 diabetes and reduced renal function without overt proteinuria are scarce. RESEARCH DESIGN AND METHODS We retrospectively assessed 526 patients with type 2 diabetes and reduced renal function (estimated glomerular filtration rate [eGFR] RESULTS Eighty-two patients with nonproteinuria (urine albumin-to-creatinine ratio [UACR] CONCLUSIONS Patients with nonproteinuric diabetic kidney disease had better-controlled blood pressure and fewer typical morphological changes and were at lower risk of CKD progression and all-cause mortality.

Background Biopsy-based studies on nephrosclerosis are lacking and the clinicopathological predictors for progression of chronic kidney disease (CKD) are not well established. Methods We retrospectively assessed 401 patients with biopsy-proven nephrosclerosis in Japan. Progression of CKD was defined as new-onset end-stage renal disease, decrease of estimated glomerular filtration rate (eGFR) by ≥50% or doubling of serum creatinine, and the sub-distribution hazard ratio (SHR) with 95% confidence interval (CI) for CKD progression was determined for various clinical and histological characteristics in competing risks analysis. The incremental value of pathological information for predicting CKD progression was assessed by calculating Harrell’s C-statistics, the Akaike information criterion (AIC), net reclassification improvement and integrated discrimination improvement. Results During a median follow-up period of 5.3 years, 117 patients showed progression of CKD and 10 patients died before the defined kidney event. Multivariable sub-distribution hazards model identified serum albumin (SHR 0.48; 95% CI 0.35–0.67), hemoglobin A1c (SHR 0.71; 95% CI 0.54–0.94), eGFR (SHR 0.98; 95% CI 0.97–0.99), urinary albumin/creatinine ratio (UACR) (SHR 1.18; 95% CI 1.08–1.29), percentage of segmental/global glomerulosclerosis (%GS) (SHR 1.01; 95% CI 1.00–1.02) and interstitial fibrosis and tubular atrophy (IFTA) (SHR 1.52; 95% CI 1.20–1.92) as risk factors for CKD progression. The C-statistic of a model with only clinical variables was improved by adding %GS (0.790 versus 0.796, P Conclusions The study implies that in addition to the traditional markers of eGFR and UACR, we may explore the markers of serum albumin and hemoglobin A1c, which are widely available but not routinely measured in patients with nephrosclerosis, and the biopsy data, especially the data on the severity of interstitial damage, for the better prediction of CKD progression in patients with nephrosclerosis.

金沢大学医薬保健研究域医学系, Background There have been a limited number of biopsy-based studies on diabetic nephropathy, and therefore the clinical importance of renal biopsy in patients with diabetes in late-stage chronic kidney disease (CKD) is still debated. We aimed to clarify the renal prognostic value of pathological information to clinical information in patients with diabetes and advanced CKD. Methods We retrospectively assessed 493 type 2 diabetics with biopsy-proven diabetic nephropathy in four centers in Japan. 296 patients with stage 3–5 CKD at the time of biopsy were identified and assigned two risk prediction scores for end-stage renal disease (ESRD): the Kidney Failure Risk Equation (KFRE, a score composed of clinical parameters) and the Diabetic Nephropathy Score (D-score, a score integrated pathological parameters of the Diabetic Nephropathy Classification by the Renal Pathology Society (RPS DN Classification)). They were randomized 2:1 to development and validation cohort. Hazard Ratios (HR) of incident ESRD were reported with 95% confidence interval (CI) of the KFRE, D-score and KFRE+D-score in Cox regression model. Improvement of risk prediction with the addition of D-score to the KFRE was assessed using c-statistics, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results During median follow-up of 1.9 years, 194 patients developed ESRD. The cox regression analysis showed that the KFRE,D-score and KFRE+D-score were significant predictors of ESRD both in the development cohort and in the validation cohort. The c-statistics of the D-score was 0.67. The c-statistics of the KFRE was good, but its predictive value was weaker than that in the miscellaneous CKD cohort originally reported (c-statistics, 0.78 vs. 0.90) and was not significantly improved by adding the D-score (0.78 vs. 0.79, p = 0.83). Only continuous NRI was positive after adding the D-score to the KFRE (0.4%; CI: 0.0–0.8%). Conclusions We found that the predict values of the KFRE and the D-score were not as good as reported, and combining the D-score with the KFRE did not significantly improve prediction of the risk of ESRD in advanced diabetic nephropathy. To improve prediction of renal prognosis for advanced diabetic nephropathy may require different approaches with combining clinical and pathological parameters that were not measured in the KFRE and the RPS DN Classification. © 2018 Yamanouchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Background and objectives The impact of the newly proposed pathological classification by the Japan Renal Pathology Society (JRPS) on renal outcome is unclear. So we evaluated that impact and created a new pathological scoring to predict outcome using this classification. Design, setting, participants, & measurements A multicenter cohort of 493 biopsy-proven Japanese patients with diabetic nephropathy (DN) were analyzed. The association between each pathological factor—Tervaert’ and JRPS classifications—and renal outcome (dialysis initiation or 50% eGFR decline) was estimated by adjusted Cox regression. The overall pathological risk score (J-score) was calculated, whereupon its predictive ability for 10-year risk of renal outcome was evaluated. Results The J-scores of diffuse lesion classes 2 or 3, GBM doubling class 3, presence of mesangiolysis, polar vasculosis, and arteriolar hyalinosis were, respectively, 1, 2, 4, 1, and 2. The scores of IFTA classes 1, 2, and 3 were, respectively, 3, 4, and 4, and those of interstitial inflammation classes 1, 2, and 3 were 5, 5, and 4 (J-score range, 0–19). Renal survival curves, when dividing into four J-score grades (0–5, 6–10, 11–15, and 16–19), were significantly different from each other (p

The prevention of relapse and infection complications during remission maintenance therapy is required to improve the prognosis of patients with microscopic polyangiitis (MPA) showing rapidly progressive glomerulonephritis (RPGN). The clinicopathological characteristics of patients with ANCA-positive MPA were examined to determine the risk factors for relapse or infectious complications after remission induction therapy. The study population consisted of 52 patients diagnosed as ANCA-positive MPA showing RPGN from 2002 to 2012, after publication of the Japanese guideline for RPGN. The clinicopathological findings were examined between the presence and absence of relapse or infectious complications. The value of vasculitis damage index (VDI) was high for the relapse group and VDI value was identified as the leading factor associated with relapse [hazard ratio (HR) 3.36, 95 % confidence interval (CI) 1.58–7.12, P

Reduced GFR in patients with CKD causes systemic accumulation of uremic toxins, which has been correlated with disease progression and increased morbidity. The orally administered spherical carbon adsorbent AST-120 reduces systemic toxin absorption through gastrointestinal sequestration, which may slow disease progression in these patients. The multinational, randomized, double-blind, placebo-controlled Evaluating Prevention of Progression in CKD (EPPIC)-1 and EPPIC-2 trials evaluated the effects of AST-120 on the progression of CKD when added to standard therapy. We randomly assigned 2035 adults with moderate to severe disease (serum creatinine at screening, 2.0-5.0 mg/dl for men and 1.5-5.0 mg/dl for women) to receive either placebo or AST-120 (9 g/d). The primary end point was a composite of dialysis initiation, kidney transplantation, and serum creatinine doubling. Each trial continued until accrual of 291 primary end points. The time to primary end point was similar between the AST-120 and the placebo groups in both trials (EPPIC-1: hazard ratio, 1.03; 95% confidence interval, 0.84 to 1.27; P=0.78) (EPPIC-2: hazard ratio, 0.91; 95% confidence interval, 0.74 to 1.12; P=0.37); a pooled analysis of both trials showed similar results. The estimated median time to primary end points for the placebo groups was 124 weeks for power calculations, but actual times were 189.0 and 170.3 weeks for EPPIC-1 and EPPIC-2, respectively. Thus, disease progression was more gradual than expected in the trial populations. In conclusion, the benefit of adding AST-120 to standard therapy in patients with moderate to severe CKD is not supported by these data.

Carotid echo indexes [intima-media thickness (IMT)] are commonly used surrogate markers for cardiovascular disease; however, the impacts of chronic kidney disease (CKD) on changes in IMT are unclear. We examined associations between CKD and IMT in participants with and without type 2 diabetes through longitudinal analysis.In total, 424 subjects were enrolled in this study. IMT was measured as per carotid echo indexes. Relationships between IMT and risk factors were analyzed using multiple linear regression analysis, in which we defined IMT as the dependent variable and atherosclerosis-related factors (age, sex, systolic pressure, total cholesterol, body mass index, estimated glomerular filtration rate (eGFR), uric acid, smoking index, number of antihypertensive drugs, statin use, urinary protein levels, past cardiovascular event, glycated hemoglobin, and diabetes duration) as independent variables.The study population was composed of 70.3 % male subjects. Participants with diabetes accounted for 64.4 % of the total population. The mean follow-up duration was 2.2 ± 1.5 years. Alterations in IMT tended to be associated with systolic blood pressure (+10 mmHg) (β = -0.0084, p = 0.09) and eGFR (+10 mL/min/1.73 m(2)) (β = -0.0049, p = 0.06) in all participants. In participants without diabetes, alterations in IMT were associated with eGFR (+10 mL/min/1.73 m(2)) (β = -0.0104, p = 0.03) and tended to be associated with systolic blood pressure (+10 mmHg) (β = 0.0094, p = 0.06). No significant relationships were found in participants with diabetes.Low eGFR was associated with progression of carotid thickness independent of common cardiovascular risk factors in non-diabetic participants.

Calciphylaxis is a life-threatening complication of end-stage kidney disease (ESKD) and leads to cutaneous necrosis and gangrene. Various risk factors for calciphylaxis have been reported, and warfarin therapy is a particularly strong trigger. Here we report the case of 50-year-old woman with ESKD and systemic lupus erythematosus who developed calciphylaxis after anti-thrombotic therapy, including warfarin, for ischemic skin ulcers due to arteriosclerosis obliterans and anti-phospholipid antibody syndrome. Although warfarin improved the thrombotic skin ulcers, it might also be a trigger for calciphylaxis. Discontinuation of the warfarin and the addition of low-density lipoprotein apheresis and sodium thiosulfate infusion failed to improve the gangrene; eventually, her legs had to be amputated to prevent lethal infection. The histology of the dermal and soft tissue obtained from the amputated legs showed typical findings of calciphylaxis. Warfarin is a vitamin K antagonist with inhibitory effects on the calcification of regulatory proteins, such as matrix Gla protein and fetuin-A. Therefore, the warfarin therapy might have induced calciphylaxis in our patient.

Diabetic kidney disease is the major cause of end-stage kidney disease in developed countries. However, the onset of kidney disorder and the progression pattern of kidney dysfunction and proteinuria greatly vary cases by cases. Therefore, risk classification with clinical data and pathological findings is important. Recent clinico-pathological study with kidney biopsy samples from diabetic patients revealed that pathological changes of diabetic nephropathy are characteristic and have special impacts on prognosis in each clinical stage. Moreover, comparison of the clinico-pathological findings of diabetic nephropathy with hypertensive nephrosclerosis revealed that there are few differences in their pathological findings in cases with low albuminuria and preserved estimated glomerular filtration rate (eGFR). Because it is so difficult to clearly distinguish pure kidney lesions caused by diabetes and kidney lesions due to effects other than diabetes, it is vital that these overlapped pathological findings be confirmed on kidney biopsy in cases of early stage diabetes. Further research is warranted regarding the pathogenesis of diabetic nephropathy and indication of kidney biopsy in diabetic cases.