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1. Evaluating the associations between compliance with CKD guideline component metrics and renal outcomes

Author

Zannatun Nyma, Kaori Kitaoka, Yuichiro Yano, Hiroshi Kanegae, Nomin Bayaraa, Seiji Kishi, Hajime Nagasu, Toshiaki Nakano, Jun Wada, Shoichi Maruyama, Naoki Nakagawa, Kouichi Tamura, Takashi Yokoo, Motoko Yanagita, Ichiei Narita, Kunihiro Yamagata, Takashi Wada, Kazuhiko Tsuruya, Naoki Nakashima, Yoshitaka Isaka, Masaomi Nangaku, Naoki Kashihara, Hirokazu Okada, and J-CKD-DB study collaborative

Subjects
CKD, Real-world clinical scenarios, Compliance to guidelines, Clinical questions, End-stage kidney disease, Medicine, Science
Abstract

Abstract Understanding the association between compliance to the Chronic Kidney Disease (CKD) guidelines in real-world clinical settings and renal outcomes remains a critical gap in knowledge. A comprehensive analysis was conducted using data from a national, multicenter CKD registry. This study included 4,455 patients with an estimated glomerular filtration rate (eGFR) measurement on the index date and eight additional metrics recorded within six months. These metrics comprised serum electrolyte levels, low-density lipoprotein cholesterol, hemoglobin, and the use of renin-angiotensin system inhibitors. The primary outcome was a composite of renal events, defined by a decline in eGFR to 5.4 mmol/L) were associated with increased event rates compared to lower levels. Similarly, low serum sodium-chloride levels ( 7.0 mg/dL) were also linked to increased events. Conversely, higher hemoglobin levels (≥ 13 g/dL) were associated with lower event rates. Compliance to guidelines, categorized into quartiles based on the number of met metrics, revealed a significantly reduced risk of events in the highest compliance group (meeting 8 metrics) compared to the lowest (0–5 metrics). Compliance to CKD guidelines in clinical practice is significantly associated with improved renal outcomes, emphasizing the need for guideline-concordant care in the management of CKD.

Published
2024
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2. Effectiveness of DialBetesPlus, a self-management support system for diabetic kidney disease: Randomized controlled trial

Author

Kayo Waki, Mitsuhiko Nara, Syunpei Enomoto, Makiko Mieno, Eiichiro Kanda, Akiko Sankoda, Yuki Kawai, Kana Miyake, Hiromichi Wakui, Yuya Tsurutani, Nobuhito Hirawa, Tadashi Yamakawa, Shiro Komiya, Akihiro Isogawa, Shinobu Satoh, Taichi Minami, Tamio Iwamoto, Tatsuro Takano, Yasuo Terauchi, Kouichi Tamura, Toshimasa Yamauchi, Masaomi Nangaku, Naoki Kashihara, and Kazuhiko Ohe

Subjects
Computer applications to medicine. Medical informatics, R858-859.7
Abstract

Abstract We evaluated the effectiveness of a mobile health (mHealth) intervention for diabetic kidney disease patients by conducting a 12-month randomized controlled trial among 126 type 2 diabetes mellitus patients with moderately increased albuminuria (urinary albumin-to-creatinine ratio (UACR): 30-299 mg/g creatinine) recruited from eight clinical sites in Japan. Using a Theory of Planned Behavior (TPB) behavior change theory framework, the intervention provides patients detailed information in order to improve patient control over exercise and dietary behaviors. In addition to standard care, the intervention group received DialBetesPlus, a self-management support system allowing patients to monitor exercise, blood glucose, diet, blood pressure, and body weight via a smartphone application. The primary outcome, change in UACR after 12 months (used as a surrogate measure of renal function), was 28.8% better than the control group’s change (P = 0.029). Secondary outcomes also improved in the intervention group, including a 0.32-point better change in HbA1c percentage (P = 0.041). These improvements persisted when models were adjusted to account for the impacts of coadministration of drugs targeting albuminuria (GLP-1 receptor agonists, SGLT-2 inhibitors, ACE inhibitors, and ARBs) (UACR: −32.3% [95% CI: −49.2%, −9.8%] between-group difference in change, P = 0.008). Exploratory multivariate regression analysis suggests that the improvements were primarily due to levels of exercise. This is the first trial to show that a lifestyle intervention via mHealth achieved a clinically-significant improvement in moderately increased albuminuria.

Published
2024
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3. Kidney outcomes of SGLT2 inhibitors among older patients with diabetic kidney disease in real-world clinical practice: the Japan Chronic Kidney Disease Database Ex

Author

Kaori Kitaoka, Yuichiro Yano, Naoki Kashihara, Hajime Nagasu, Hiroshi Kanegae, Noriharu Chishima, Hiroki Akiyama, and Kouichi Tamura

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Introduction We compared the kidney outcomes between patients with diabetic kidney disease (DKD) aged ≥75 years initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors versus other glucose-lowering drugs, additionally presenting with or without proteinuria.Research design and methods Using the Japan Chronic Kidney Disease Database, we developed propensity scores, implementing a 1:1 matching protocol. The primary outcome included the decline rate in estimated glomerular filtration rate (eGFR), and secondary outcomes incorporated a composite of a 40% reduction in eGFR or progression to end-stage kidney disease.Results At baseline, the mean age at initiation of SGLT2 inhibitors (n=348) or other glucose-lowering medications (n=348) was 77.7 years. The mean eGFR was 59.3 mL/min/1.73m2 and proteinuria was 230 (33.0%) patients. Throughout the follow-up period, the mean annual rate of eGFR change was −0.80 mL/min/1.73 m2/year (95% CI −1.05 to −0.54) among SGLT2 inhibitors group and −1.78 mL/min/1.73 m2/year (95% CI −2.08 to −1.49) in other glucose-lowering drugs group (difference in the rate of eGFR decline between the groups was 0.99 mL/min/1.73 m2/year (95% CI 0.5 to 1.38)), favoring SGLT2 inhibitors (p

Published
2024
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4. New marker for chronic kidney disease progression and mortality in medical-word virtual space

Author

Eiichiro Kanda, Bogdan I. Epureanu, Taiji Adachi, Tamaki Sasaki, and Naoki Kashihara

Subjects
Medicine, Science
Abstract

Abstract A new marker reflecting the pathophysiology of chronic kidney disease (CKD) has been desired for its therapy. In this study, we developed a virtual space where data in medical words and those of actual CKD patients were unified by natural language processing and category theory. A virtual space of medical words was constructed from the CKD-related literature (n = 165,271) using Word2Vec, in which 106,612 words composed a network. The network satisfied vector calculations, and retained the meanings of medical words. The data of CKD patients of a cohort study for 3 years (n = 26,433) were transformed into the network as medical-word vectors. We let the relationship between vectors of patient data and the outcome (dialysis or death) be a marker (inner product). Then, the inner product accurately predicted the outcomes: C-statistics of 0.911 (95% CI 0.897, 0.924). Cox proportional hazards models showed that the risk of the outcomes in the high-inner-product group was 21.92 (95% CI 14.77, 32.51) times higher than that in the low-inner-product group. This study showed that CKD patients can be treated as a network of medical words that reflect the pathophysiological condition of CKD and the risks of CKD progression and mortality.

Published
2024
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5. IL-1β may be an indicator of peritoneal deterioration after healing of peritoneal dialysis-associated peritonitis

Author

Akira Hirano, Hiroyuki Kadoya, Yu Yamanouchi, Seiji Kishi, Tamaki Sasaki, and Naoki Kashihara

Subjects
Chronic inflammation, IL-1β, Inflammasome, Peritoneal dialysis, Peritonitis, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Abstract Background Peritoneal dialysis (PD) is an essential lifesaving treatment for end-stage renal disease. However, PD therapy is limited by peritoneal inflammation, which leads to peritoneal membrane failure because of progressive peritoneal deterioration. Peritonitis is the most common complication in patients undergoing PD. Thus, elucidating the mechanism of chronic peritoneal inflammation after PD-associated peritonitis is an urgent issue for patients undergoing PD. This first case report suggests that an increased interleukin-1β (IL-1β) expression in the peritoneal dialysate after healing of peritonitis can contribute to peritoneal deterioration. Case presentation A 64-year-old woman was diagnosed with diabetes mellitus 10 years ago and had been started on PD for end-stage renal disease. One day, the patient developed PD-associated acute peritonitis and was admitted to our hospital for treatment. Thus, treatment with antimicrobial agents was initiated for PD-associated peritonitis. Dialysate turbidity gradually disappeared after treatment with antimicrobial agents, and the number of cells in the PD fluid decreased. After 2 weeks of antimicrobial therapy, peritonitis was clinically cured, and the patient was discharged. Thereafter, the patient did not develop peritonitis; however, residual renal function tended to decline, and peritoneal function also decreased in a relatively short period. We evaluated pro-inflammatory cytokine levels before and after PD-associated peritonitis; interestingly, the levels of IL-1β remained high in the PD fluid, even after remission of bacterial peritonitis. In addition, it correlated with decreased peritoneal function. Conclusions This case suggests that inflammasome-derived pro-inflammatory cytokines may contribute to chronic inflammation-induced peritoneal deterioration after PD-related peritonitis is cured.

Published
2023
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6. Author Correction: Effectiveness of DialBetesPlus, a self-management support system for diabetic kidney disease: Randomized controlled trial

Author

Kayo Waki, Mitsuhiko Nara, Syunpei Enomoto, Makiko Mieno, Eiichiro Kanda, Akiko Sankoda, Yuki Kawai, Kana Miyake, Hiromichi Wakui, Yuya Tsurutani, Nobuhito Hirawa, Tadashi Yamakawa, Shiro Komiya, Akihiro Isogawa, Shinobu Satoh, Taichi Minami, Tamio Iwamoto, Tatsuro Takano, Yasuo Terauchi, Kouichi Tamura, Toshimasa Yamauchi, Masaomi Nangaku, Naoki Kashihara, and Kazuhiko Ohe

Subjects
Computer applications to medicine. Medical informatics, R858-859.7
Published
2024
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7. The Impact of Potassium Binders on Mortality in Patients with Hyperkalemia: A Single-Center Study

Author

Hajime Nagasu, Atsuyuki Tokuyama, Eiichiro Kanda, Seiji Itano, Seiji Kishi, Tamaki Sasaki, and Naoki Kashihara

Subjects
chronic kidney disease, electronic medical record, hyperkalemia, potassium binder, Internal medicine, RC31-1245
Abstract

Hyperkalemia is associated with an increased risk of mortality and is a common complication in patients with chronic kidney disease (CKD). Despite the prevalence of hyperkalemia, current real-world data suggest that serum potassium levels are not effectively managed in clinical practice. The potential benefit of potassium binders in reducing the risk of death has not been thoroughly investigated. Therefore, this retrospective cohort study aimed to investigate the potential impact of potassium binders on mortality risk in patients with CKD by analyzing electronic medical records. The study included 1689 patients with CKD and hyperkalemia (serum potassium level > 5.0 mEq/L), who visited Kawasaki Medical School Hospital between January 2014 and December 2018. The patients were divided into two groups: those without CPS (calcium polystyrene sulphonate) treatment (CPS_OFF) and those with CPS treatment (CPS_ON). The results showed that the incidence of death was significantly higher in the CPS_OFF group than in the CPS_ON group (22.3% vs. 19.6%, p < 0.001). After propensity score matching, the CPS_ON group had a higher survival rate than the CPS_OFF group (log-rank test, p = 0.020). These results suggest that potassium binders may reduce the risk of death in patients with CKD and hyperkalemia. We hope that the results of this cohort study will be confirmed in future RCTs.

Published
2023
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8. Effect of the Diabetic Nephropathy Aggravation Prevention Program on medical visit behavior in individuals under the municipal national health insurance

Author

Asuka Ikeda, Makoto Fujii, Yuko Ohno, Kayo Godai, Yaya Li, Yuko Nakamura, Daisuke Yabe, Kazuyo Tsushita, Naoki Kashihara, Kei Kamide, and Mai Kabayama

Subjects
Health insurance claims, Medical visit behavior, National database, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

ABSTRACT Aims/Introduction We aimed to clarify the effectiveness of the Diabetic Nephropathy Aggravation Prevention Program in Japan by comparing the diabetes‐related medical visit behavior of individuals under the municipal national health insurance according to insurers' effort levels. Materials and Methods We assessed changes in medical visit behavior according to insurers' effort levels, “Full Efforts,” “Some Efforts” and “No Effort,” using longitudinal data from the National Database of Health Insurance Claims and Specific Health Checkups before 2015 and after 2018 regarding the national health insurance programs in Japan. We analyzed the effect of the Diabetic Nephropathy Aggravation Prevention Program using a generalized linear mixed model for 208,388 participants with diabetes. Results The additive effect on medical visit behavior was significantly higher for insurers with “Full Efforts” than for those with “No Effort;” the coefficient (log odds ratio) was 0.159 (95% confidence interval 0.063–0.256). The additive effects on medical visit behavior sizes for the people with hemoglobin A1c ≥7.0%, positive urinary protein and systolic blood pressure ≥140 mmHg were 0.508, 0.402 and 0.232, respectively, which were larger than the overall effect size (0.159) for insurers with “Full Efforts.” Conclusions Our findings showed that insurer efforts had an additive effect on the increase in the number of medical visits, suggesting that this national program could reduce the number of end‐stage renal failures or dialysis in Japan.

Published
2023
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9. Targeting the Alternative Complement Pathway With Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study

Author

Dana V. Rizk, Brad H. Rovin, Hong Zhang, Naoki Kashihara, Bart Maes, Hernán Trimarchi, Vlado Perkovic, Matthias Meier, Dmitrij Kollins, Olympia Papachristofi, Alan Charney, and Jonathan Barratt

Subjects
alternative complement pathway, eGFR slope, Factor B, IgAN, iptacopan (LNP023), proteinuria, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Introduction: Targeting the alternative complement pathway (AP) is an attractive therapeutic strategy because of its role in immunoglobulin A nephropathy (IgAN) pathophysiology. Iptacopan (LNP023), a proximal complement inhibitor that specifically binds to factor B and inhibits the AP, reduced proteinuria and attenuated AP activation in a Phase 2 study of patients with IgAN, thereby supporting the rationale for its evaluation in a Phase 3 study. Methods: APPLAUSE-IgAN (NCT04578834) is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 3 study enrolling approximately 450 adult patients (aged ≥18 years) with biopsy-confirmed primary IgAN at high risk of progression to kidney failure despite optimal supportive treatment. Eligible patients receiving stable and maximally tolerated doses of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) will be randomized 1:1 to either iptacopan 200 mg or placebo twice daily for a 24-month treatment period. A prespecified interim analysis (IA) will be performed when approximately 250 patients from the main study population complete the 9-month visit. The primary objective is to demonstrate superiority of iptacopan over placebo in reducing 24-hour urine protein-to-creatinine ratio (UPCR) at the IA and demonstrate the superiority of iptacopan over placebo in slowing the rate of estimated glomerular filtration rate (eGFR) decline (total eGFR slope) estimated over 24 months at study completion. The effect of iptacopan on patient-reported outcomes, safety, and tolerability will be evaluated as secondary outcomes. Conclusions: APPLAUSE-IgAN will evaluate the benefits and safety of iptacopan, a novel targeted therapy for IgAN, in reducing complement-mediated kidney damage and thus slowing or preventing disease progression.

Published
2023
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10. Development of a prognostic risk score to predict early mortality in incident elderly Japanese hemodialysis patients.

Author

Hirokazu Okada, Atsushi Ono, Koji Tomori, Tsutomu Inoue, Norio Hanafusa, Ken Sakai, Ichiei Narita, Toshiki Moriyama, Yoshitaka Isaka, Kei Fukami, Seiji Itano, Eiichiro Kanda, and Naoki Kashihara

Subjects
Medicine, Science
Abstract

BackgroundInformation of short-term prognosis after hemodialysis (HD) introduction is important for elderly patients with chronic kidney disease (CKD) and their families choosing a modality of renal replacement therapy. Therefore, we developed a risk score to predict early mortality in incident elderly Japanese hemodialysis patients.Materials and methodsWe analyzed data of incident elderly HD patients from a nationwide cohort study of the Japanese Society for Dialysis Therapy Renal Data Registry (JRDR) to develop a prognostic risk score. Candidate risk factors for early death within 1 year was evaluated using multivariate logistic regression analysis. The risk score was developed by summing up points derived from parameter estimate values of independent risk factors. The association between risk score and early death was tested using Cox proportional hazards models. This risk score was validated twice by using an internal validation cohort derived from the JRDR and an external validation cohort collected for this study.ResultsUsing the development cohort (n = 2,000), nine risk factors were retained in the risk score: older age (>85), yes = 2, no = 0; sex, male = 2, female = 0; lower body mass index (2.0 mg/dL), yes = 2, no = 0. In the internal and external validation cohorts (n = 739, 140, respectively), the medium- and high-risk groups (total score, 6 to 10 and 11 or more, respectively) showed significantly higher risk of early death than the low-risk group (total score, 0 to 5) (pConclusionWe developed a prognostic risk score predicting early death within 1 year in incident elderly Japanese HD patients, which may help detect elderly patients with a high-risk of early death after HD introduction.

Published
2024
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11. Reduction in the magnitude of serum potassium elevation in combination therapy with esaxerenone (CS‐3150) and sodium–glucose cotransporter 2 inhibitor in patients with diabetic kidney disease: Subanalysis of two phase III studies

Author

Kenichi Shikata, Sadayoshi Ito, Naoki Kashihara, Masaomi Nangaku, Takashi Wada, Yasuyuki Okuda, Tomoko Sawanobori, and Kotaro Sugimoto

Subjects
Esaxerenone, Potassium, Sodium–glucose transporter 2 inhibitor, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Abstract Aims/Introduction We evaluated the effect of co‐administration of esaxerenone and a sodium–glucose cotransporter 2 (SGLT2) inhibitor on the magnitude of serum potassium elevation in Japanese patients with diabetic kidney disease. Materials and Methods We carried out a prespecified subanalysis of data from two phase III studies: a multicenter, randomized, double‐blind, placebo‐controlled trial in patients with type 2 diabetes and microalbuminuria (J308); and a multicenter, single‐arm, open‐label trial in patients with type 2 diabetes and macroalbuminuria (J309). Changes in serum potassium levels during the studies and other measures were evaluated according to SGLT2 inhibitor use. Results In both studies, time‐course changes in serum potassium levels, and incidence rates of serum potassium elevation were lower in patients with co‐administration of SGLT2 inhibitor in both the placebo and esaxerenone groups than those without the inhibitor. In contrast, time‐course changes and mean percentage changes from baseline in urinary albumin‐to‐creatinine ratio, the proportion of patients with albuminuria remission and time‐course changes in blood pressure did not change with or without SGLT2 inhibitor, whereas the albumin‐to‐creatinine ratio and blood pressure were reduced with esaxerenone. The blood glucose‐lowering effect of SGLT2 inhibitor was not affected by esaxerenone. Conclusions In Japanese patients with type 2 diabetes and albuminuria treated with esaxerenone, concomitant use of SGLT2 inhibitor reduced the magnitude of serum potassium elevation without any change of its antihypertensive and albuminuria‐suppressing effects. Co‐administration of esaxerenone and SGLT2 inhibitor might be a beneficial treatment option for patients with diabetic kidney disease.

Published
2022
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13. Machine-learning-based Web system for the prediction of chronic kidney disease progression and mortality.

Author

Eiichiro Kanda, Bogdan Iuliu Epureanu, Taiji Adachi, and Naoki Kashihara

Subjects
Computer applications to medicine. Medical informatics, R858-859.7
Abstract

Chronic kidney disease (CKD) patients have high risks of end-stage kidney disease (ESKD) and pre-ESKD death. Therefore, accurately predicting these outcomes is useful among CKD patients, especially in those who are at high risk. Thus, we evaluated whether a machine-learning system can predict accurately these risks in CKD patients and attempted its application by developing a Web-based risk-prediction system. We developed 16 risk-prediction machine-learning models using Random Forest (RF), Gradient Boosting Decision Tree, and eXtreme Gradient Boosting with 22 variables or selected variables for the prediction of the primary outcome (ESKD or death) on the basis of repeatedly measured data of CKD patients (n = 3,714; repeatedly measured data, n = 66,981) in their electronic-medical records. The performances of the models were evaluated using data from a cohort study of CKD patients carried out over 3 years (n = 26,906). One RF model with 22 variables and another RF model with 8 variables of time-series data showed high accuracies of the prediction of the outcomes and were selected for use in a risk-prediction system. In the validation, the 22- and 8-variable RF models showed high C-statistics for the prediction of the outcomes: 0.932 (95% CI 0.916, 0.948) and 0.93 (0.915, 0.945), respectively. Cox proportional hazards models using splines showed a highly significant relationship between the high probability and high risk of an outcome (p

Published
2023
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14. The associations of the national health and productivity management program with corporate profits in Japan

Author

Yuichiro Yano, Hiroshi Kanegae, Koichi Node, Atsushi Mizuno, Akira Nishiyama, Hiromi Rakugi, Hiroshi Itoh, Kaori Kitaoka, Naoki Kashihara, Fumiaki Ikeno, Ichiro Tsuji, and Kunio Okada

Subjects
health and productivity management, smoking, lifestyle, Medicine
Abstract

OBJECTIVES Using a dataset from a survey on national health and productivity management, we identified health and productivity factors associated with organizational profitability. METHODS The Ministry of Economy, Trade and Industry conducted an annual survey on Health and Productivity Management between 2014 and 2021. We assessed the associations of organizational health and productivity management using survey questions collected in 2017 and 2018, with the rate of change in profits from 2017 and 2018 to 2020. We identified factors associated with organizational profitability using eXtreme Gradient Boosting, and calculated SHapley Additive exPlanation (SHAP) values for each factor. RESULTS Among 1,593 companies (n= 4,359,834 employees), the mean age of employees at baseline was 40.3 years and the proportion of women was 25.8%. A confusion matrix for evaluating model performance had an accuracy of 0.997, precision of 0.993, recall of 0.997, and area under the precision-recall curve of 0.999. The most important factors related to an increase in corporate profits were the percentage of current smokers (SHAP value, 0.121), per-employee cost of health services (0.084) and medical services (0.050); the percentage of full-time employees working in sales departments (0.074) and distribution or customer service departments (0.054); the percentage of employees who slept well (0.055); and the percentage of employees within a company who regularly exercised (0.043). CONCLUSIONS Employees’ lifestyle-related health risk factors and organizations’ management systems were associated with organizational profitability. Lifestyle medicine professionals may demonstrate a significant return on investment by creating a healthier and more productive workforce.

Published
2022
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15. Infection prevention measures for patients undergoing hemodialysis during the COVID-19 pandemic in Japan: a nationwide questionnaire survey

Author

Yuka Sugawara, Masao Iwagami, Kan Kikuchi, Yoko Yoshida, Ryoichi Ando, Toshio Shinoda, Munekazu Ryuzaki, Hidetomo Nakamoto, Ken Sakai, Norio Hanafusa, Naoki Kashihara, Masaomi Nangaku, and On behalf of COVID-19 Task Force Committee of the Japanese Association of Dialysis Physicians, the Japanese Society for Dialysis Therapy, and the Japanese Society of Nephrology

Subjects
COVID-19, SARS-CoV-2, Pandemic, Hemodialysis, Infection prevention measures, PPEs, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Abstract Background Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic affecting a variety of medical treatments, including hemodialysis. This study aims to investigate the implementation of infection control measures, to examine the shortage of personal protective equipment (PPE) and disinfectants, and to quantify the number of nosocomial COVID-19 transmissions in hemodialysis facilities in Japan during the pandemic. Methods We conducted a nationwide questionnaire survey between 20 October and 16 November 2020 (i.e., between the “second wave” and “third wave” in Japan) in the 4198 dialysis facilities of the Japanese Association of Dialysis Physicians and the Japanese Society for Dialysis Therapy. A total of 2227 facilities (53.0%) responded. The questionnaire consisted of (i) characteristics of facilities, (ii) infection prevention measures in routine dialysis practices, (iii) shortage of PPE, (iv) feasibility of various isolation measures, and (v) nosocomial transmission. Results Half of the responding facilities were hospitals with multiple departments, and the other half were clinics specialized in dialysis. Several infection prevention measures such as health checks of staff and patients, donning of masks before and after hemodialysis, and disinfection of frequently contacted areas were implemented during the COVID-19 pandemic. There was a significant improvement in the implementation rate of these measures during the pandemic, compared to before it, which reached over 90%. More than half of the facilities reported a shortage of disposable masks (67.2%) and hand sanitizer alcohol (56.7%). Isolation of COVID-19 patients in private rooms was possible only in 52.7% of the facilities. The majority of facilities (73.3%) could not accept COVID-19 dialysis patients due to lack of space and manpower. Nosocomial transmission of COVID-19 occurred in 4.0% of the facilities. Of those infected, 51.9% were staff. Conclusions This survey revealed that most hemodialysis facilities in Japan had improved implementation of infection control measures and had shortage of PPEs and disinfectants, though some facilities did not implement infection prevention measures adequately, mainly due to the limited space of the facility. It may be recommended that each facility immediately establishes isolation measures to prepare for the pandemic of COVID-19.

Published
2021
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16. Cardiovascular and Renal Outcomes Associated With Hyperkalemia in Chronic Kidney Disease: A Hospital-Based Cohort Study

Author

Shun Kohsaka, MD, Suguru Okami, PhD, Eiichiro Kanda, MD, PhD, MPH, Naoki Kashihara, MD, PhD, and Toshitaka Yajima, MD, PhD

Subjects
Medicine (General), R5-920
Abstract

Objective: To examine the association between hyperkalemia and long-term cardiovascular and renal outcomes in patients with chronic kidney disease. Patients and Methods: An observational retrospective cohort study was performed using a Japanese hospital claims registry, Medical Data Vision (April 1, 2008, to September 30, 2018). Of 1,208,894 patients with at least 1 potassium measurement, 167,465 patients with chronic kidney disease were selected based on International Classification of Diseases, Tenth Revision codes or estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2. Hyperkalemia was defined as at least 2 potassium measurements of 5.1 mmol/L or greater within 12 months. Normokalemic controls were patients without a record of potassium levels of 5.1 mmol/L or greater and 3.5 mmol/L or less. Changes in eGFRs and hazard ratios of death, hospitalization for cardiac events, heart failure, and renal replacement therapy introduction were assessed between propensity score–matched hyperkalemic patients and normokalemic controls. Results: Of 16,133 hyperkalemic patients and 11,898 normokalemic controls eligible for analyses, 5859 (36.3%) patients and 5859 (49.2%) controls were selected after propensity score matching. The mean follow-up period was 3.5 years. The 3-year eGFR change in patients and controls was −5.75 and −1.79 mL/min/1.73 m2, respectively. Overall, hyperkalemic patients had higher risks for death, hospitalization for cardiac events, heart failure, and renal replacement therapy introduction than controls, with hazard ratios of 4.40 (95% CI, 3.74 to 5.18), 1.95 (95% CI, 1.59 to 2.39), 5.09 (95% CI, 4.17 to 6.21), and 7.54 (95% CI, 5.73 to 9.91), respectively. Conclusion: Hyperkalemia was associated with significant risks for mortality and adverse clinical outcomes, with more rapid decline of renal function. These findings underscore the significance of hyperkalemia as a predisposition to future adverse events in patients with chronic kidney disease.

Published
2021
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17. Efficacy of the Self-management Support System DialBetesPlus for Diabetic Kidney Disease: Protocol for a Randomized Controlled Trial

Author

Yuki Kawai, Akiko Sankoda, Kayo Waki, Kana Miyake, Aki Hayashi, Makiko Mieno, Hiromichi Wakui, Yuya Tsurutani, Jun Saito, Nobuhito Hirawa, Tadashi Yamakawa, Shiro Komiya, Akihiro Isogawa, Shinobu Satoh, Taichi Minami, Uru Osada, Tamio Iwamoto, Tatsuro Takano, Yasuo Terauchi, Kouichi Tamura, Toshimasa Yamauchi, Takashi Kadowaki, Masaomi Nangaku, Naoki Kashihara, and Kazuhiko Ohe

Subjects
Medicine, Computer applications to medicine. Medical informatics, R858-859.7
Abstract

BackgroundDiabetic kidney disease (DKD) is one of the main complications of type 2 diabetes mellitus (T2DM). DKD is a known risk factor for end-stage renal disease, cardiovascular disease, and all-cause death. Effective intervention for early-stage DKD is vital to slowing down the progression of kidney disease and improve prognoses. Mobile health (mHealth) is reportedly effective in supporting patients’ self-care and improving glycemic control, but the impact of mHealth on DKD has yet to be shown. ObjectiveThe purpose of this study is to evaluate the efficacy of standard therapy with the addition of a self-management support system, DialBetesPlus, in patients with DKD and microalbuminuria. MethodsThis study is a prospective, randomized, open-label, multicenter clinical trial. The target population consists of 160 patients diagnosed with T2DM accompanied by microalbuminuria. We randomly assigned the patients to 2 groups—the intervention group using DialBetesPlus in addition to conventional therapy and the control group using conventional therapy alone. DialBetesPlus is a smartphone application that supports patients’ self-management of T2DM. The study period was 12 months, with a follow-up survey at 18 months. The primary outcome was a change in albuminuria levels at 12 months. Secondary outcomes included changes in physical parameters, blood test results (glycemic control, renal function, and lipid metabolism), lifestyle habits, self-management scores, medication therapy, and quality of life. ResultsThe study was approved in April 2018. We began recruiting patients in July 2018 and completed recruiting in August 2019. The final 18-month follow-up was conducted in March 2021. We recruited 159 patients and randomly allocated 70 into the intervention group and 61 into the control group, with 28 exclusions due to withdrawal of consent, refusal to continue, or ineligibility. The first results are expected to be available in 2021. ConclusionsThis is the first randomized controlled trial assessing the efficacy of mHealth on early-stage DKD. We expect that albuminuria levels will decrease significantly in the intervention group due to improved glycemic control with ameliorated self-care behaviors. Trial RegistrationUMIN-CTR UMIN000033261; https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000037924 International Registered Report Identifier (IRRID)DERR1-10.2196/31061

Published
2021
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18. Hyperkalemia in Real-World Patients Under Continuous Medical Care in Japan

Author

Naoki Kashihara, Shun Kohsaka, Eiichiro Kanda, Suguru Okami, and Toshitaka Yajima

Subjects
Diseases of the genitourinary system. Urology, RC870-923
Abstract

Introduction: An abnormal serum potassium (S-K) level is an important electrolyte disturbance. However, its relation to clinical outcomes in real-world patients, particularly hyperkalemia burden, is not extensively studied. Methods: An observational retrospective cohort study using a Japanese hospital claims database was done (April 2008–September 2017; N = 1,022,087). Associations between index S-K level and 3-year survival were modeled using cubic spline regression. Cox regression model was applied to estimate the time to death according to different S-K levels. Prevalence, patient characteristics, treatment patterns, and management of patients with hyperkalemia from first episode were assessed. Results: Hyperkalemia prevalence was 67.9 (95% confidence interval [CI]: 67.1–68.8) per 1000 and increased in patients with chronic kidney disease (CKD) (227.9; 95% CI: 224.3–231.5), heart failure (134.0; 95% CI: 131.2–136.8), and renin-angiotensin-aldosterone system inhibitor (RAASi) use (142.2; 95% CI: 139.6–144.7). U-shaped associations between S-K level and 3-year survival were observed with nadir 4.0 mEq/l. The risk of death was increased at S-K 5.1–5.4 mEq with hazard ratio of 7.6 (95% CI: 7.2–8.0). The 3-year mortality rate in patients with CKD stages 3a, 3b, 4, and 5 with normokalemia were 1.51%, 3.93%, 10.86%, and 12.09%, whereas that in patients with CKD stage 3a at S-K 5.1–5.4, 5.5–5.9, and ≥6.0 mEq/l increased to 10.31%, 11.43%, and 22.64%, respectively. Despite treatment with loop diuretics (18.5%) and potassium binders (5.8%), >30% of patients had persistently high S-K (≥5.1 mEq/l). Conclusion: This study provides real-world insight on hyperkalemia based on a large number of patients with various medical backgrounds. Keywords: chronic kidney disease, congestive heart failure, hyperkalemia, renin-angiotensin-aldosterone inhibitor, renin angiotensin system

Published
2019
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20. Proteinuria changes in kidney disease patients with clinical remission during the COVID-19 pandemic.

Author

Nobuo Tsuboi, Takaya Sasaki, Naoki Kashihara, and Takashi Yokoo

Subjects
Medicine, Science
Abstract

BackgroundsData on how lifestyle changes due to the coronavirus disease 2019 (COVID-19) pandemic have influenced the clinical features of kidney disease patients remain scarce.MethodsThis study retrospectively analyzed clinical variables in patients with stage G1-G4 chronic kidney disease (CKD) with complete or incomplete remission of proteinuria, who were managed in a nephrology outpatient clinic of a university hospital in Tokyo. The clinical variables during the COVID-19 pandemic (term 1, June-July 2020) were compared to those one year before the pandemic (term 0, June-July 2019). The urinary protein excretion (UPE) was used as the primary outcome measure.ResultsThis study included 325 patients with stage G1-G4 CKD (mean age 58.5 years old, 37.5% female, 80.6% on renin-angiotensin aldosterone system inhibitors [RAASis], 12.0% on maintenance dose immunosuppression therapy) evaluated at term 0. The UPE at terms 0 and 1 was 247 (92-624) and 203 (84-508) mg/day [median (25th-75th percentile)], respectively; the value in term 1 was 18% lower than that in term 0 (pConclusionIn kidney disease patients receiving standard medical care from nephrologists, the UPE after the emergency declaration in relation to the COVID-19 pandemic was lower than before the declaration. The UPE reduction may be associated with reduced dietary salt intake during the pandemic in patients treated with RAASi for insufficient control of proteinuria. Our results support the current proposal to continue therapeutic approaches to these patients, which involve RAASi therapy along with optimizing dietary habits, even while dealing with the COVID-19 pandemic.

Published
2021
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21. Effect of zinc deficiency on chronic kidney disease progression and effect modification by hypoalbuminemia.

Author

Atsuyuki Tokuyama, Eiichiro Kanda, Seiji Itano, Megumi Kondo, Yoshihisa Wada, Hiroyuki Kadoya, Kengo Kidokoro, Hajime Nagasu, Tamaki Sasaki, and Naoki Kashihara

Subjects
Medicine, Science
Abstract

Serum zinc (Zn) levels tend to be low in chronic kidney disease (CKD) patients. This cohort study was conducted to investigate the relationship between zinc deficiency and CKD progression. Patients were classified into two groups based on Zn levels < 60 μg/dl (low-Zn group, n = 160) and ≥ 60 μg/dl (high-Zn group, n = 152). The primary outcome was defined as end-stage kidney disease (ESKD) or death and was examined over a 1-year observation period. Overall, the mean Zn level was 59.6 μg/dl and the median eGFR was 20.3 ml/min/1.73 m2. The incidence of the primary outcome was higher in the low-Zn group (p

Published
2021
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22. Clinical and Economic Burden of Hyperkalemia: A Nationwide Hospital-Based Cohort Study in JapanPlain-Language Summary

Author

Eiichiro Kanda, Naoki Kashihara, Shun Kohsaka, Suguru Okami, and Toshitaka Yajima

Subjects
Hyperkalemia, chronic kidney disease (CKD), heart failure (HF), healthcare cost, health economics, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Rationale & Objective: Hyperkalemia is a common electrolyte abnormality of chronic kidney disease and heart failure associated with increased mortality and morbidity. We aimed to assess the long-term economic burden of hyperkalemia. Design: Observational cohort study using a Japanese nationwide hospital claims database (April 1, 2008, to September 30, 2018). Setting & Population: : Patients 18 years or older with at least 1 serum potassium value (N = 1,208,894). Exposures: Hyperkalemia defined with the presence of at least 2 serum potassium values ≥ 5.1 mmol/L. Outcome Measures: Direct health care costs and resource use in patients with hyperkalemia within and after 12 months from first hyperkalemia episodes. Analytical Approach: Health care costs and resource use were compared with propensity score–matched or nonmatched normokalemic controls. Multivariable regression analysis was performed to examine factors associated with health care costs. Results: 27,534 patients with hyperkalemia and 233,098 normokalemic controls were studied. Mean ± SD age was 73±13 years in patients with hyperkalemia; among them, 59% and 35% had chronic kidney disease and heart failure, respectively. In the propensity score–matched cohort (n = 5,859 in each group), average numbers of hospitalizations per patient per year in patients with hyperkalemia within and after 12 months were 1.2 and 1.6 times higher, respectively, compared with those in patients with normokalemia. The total cost per patient in patients with hyperkalemia was higher than for controls, with mean differences of $8,611 (95% CI, $8,046-$9,175) within 12 months and $5,150 (95% CI, $4,733-$5,566) after 12 months. The number of repeat hyperkalemic episodes was the factor with the strongest association with long-term health care costs, whereas severity of hyperkalemia was not associated. Limitations: This study used secondary data; therefore, residual confounders may not be fully excluded. Conclusions: Hyperkalemia was associated with significant long-term economic burden with frequent hospitalizations due to recurrent episodes, indicating the importance of hyperkalemia treatment for the sake of reducing health economic burdens and clinical complications.

Published
2020
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23. Conditions, pathogenesis, and progression of diabetic kidney disease and early decliner in Japan

Author

Tomoya Mita, Yui Yoshida, Kosuke Kashiwabara, Yosuke Hirakawa, Tetsuhiro Tanaka, Shinsuke Noso, Hiroshi Ikegami, Mitsuru Ohsugi, Daisuke Koya, Koki Mise, Jun Wada, Miho Shimizu, Yumi Ito, Ichiei Narita, Naoki Kashihara, and Masaomi Nangaku

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

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)

Published
2020
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24. Application of explainable ensemble artificial intelligence model to categorization of hemodialysis-patient and treatment using nationwide-real-world data in Japan.

Author

Eiichiro Kanda, Bogdan I Epureanu, Taiji Adachi, Yuki Tsuruta, Kan Kikuchi, Naoki Kashihara, Masanori Abe, Ikuto Masakane, and Kosaku Nitta

Subjects
Medicine, Science
Abstract

BACKGROUND:Although dialysis patients are at a high risk of death, it is difficult for medical practitioners to simultaneously evaluate many inter-related risk factors. In this study, we evaluated the characteristics of hemodialysis patients using machine learning model, and its usefulness for screening hemodialysis patients at a high risk of one-year death using the nation-wide database of the Japanese Society for Dialysis Therapy. MATERIALS AND METHODS:The patients were separated into two datasets (n = 39,930, 39,930, respectively). We categorized hemodialysis patients in Japan into new clusters generated by the K-means clustering method using the development dataset. The association between a cluster and the risk of death was evaluated using multivariate Cox proportional hazards models. Then, we developed an ensemble model composed of the clusters and support vector machine models in the model development phase, and compared the accuracy of the prediction of mortality between the machine learning models in the model validation phase. RESULTS:Average age of the subjects was 65.7±12.2 years; 32.7% had diabetes mellitus. The five clusters clearly distinguished the groups on the basis of their characteristics: Cluster 1, young male, and chronic glomerulonephritis; Cluster 2, female, and chronic glomerulonephritis; Cluster 3, diabetes mellitus; Cluster 4, elderly and nephrosclerosis; Cluster 5, elderly and protein energy wasting. These clusters were associated with the risk of death; Cluster 5 compared with Cluster 1, hazard ratio 8.86 (95% CI 7.68, 10.21). The accuracy of the ensemble model for the prediction of 1-year death was 0.948 and higher than those of logistic regression model (0.938), support vector machine model (0.937), and deep learning model (0.936). CONCLUSIONS:The clusters clearly categorized patient on their characteristics, and reflected their prognosis. Our real-world-data-based machine learning system is applicable to identifying high-risk hemodialysis patients in clinical settings, and has a strong potential to guide treatments and improve their prognosis.

Published
2020
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25. Prevalences of hyperuricemia and electrolyte abnormalities in patients with chronic kidney disease in Japan: A nationwide, cross-sectional cohort study using data from the Japan Chronic Kidney Disease Database (J-CKD-DB).

Author

Tadashi Sofue, Naoki Nakagawa, Eiichiro Kanda, Hajime Nagasu, Kunihiro Matsushita, Masaomi Nangaku, Shoichi Maruyama, Takashi Wada, Yoshio Terada, Kunihiro Yamagata, Ichiei Narita, Motoko Yanagita, Hitoshi Sugiyama, Takashi Shigematsu, Takafumi Ito, Kouichi Tamura, Yoshitaka Isaka, Hirokazu Okada, Kazuhiko Tsuruya, Hitoshi Yokoyama, Naoki Nakashima, Hiromi Kataoka, Kazuhiko Ohe, Mihoko Okada, and Naoki Kashihara

Subjects
Medicine, Science
Abstract

BackgroundThe Japan Chronic Kidney Disease Database (J-CKD-DB) is a nationwide clinical database of patients with chronic kidney disease (CKD) based on electronic health records. The objective of this study was to assess the prevalences of hyperuricemia and electrolyte abnormalities in Japanese patients with CKD.MethodsIn total, 35,508 adult outpatients with estimated glomerular filtration rates of 5-60 ml/min/1.73 m2 in seven university hospitals were included this analysis. The proportions of patients with CKD stages G3b, G4, and G5 were 23.5%, 7.6%, and 3.1%, respectively.ResultsLogistic regression analysis showed that prevalence of hyperuricemia was associated with CKD stages G3b (adjusted odds ratio [95% confidence interval]: 2.12 [1.90-2.37]), G4 (4.57 [3.92-5.32]), and G5 (2.25 [1.80-2.80]). The respective prevalences of hyponatremia, hypercalcemia, hyperphosphatemia, and narrower difference between serum sodium and chloride concentrations were elevated in patients with CKD stages G3b, G4, and G5, compared with those prevalences in patients with CKD stage G3a. The prevalences of hyperkalemia were 8.3% and 11.6% in patients with CKD stages G4 and G5, respectively. In patients with CKD stage G5, the proportions of patients with optimal ranges of serum uric acid, potassium, corrected calcium, and phosphate were 49.6%, 73.5%, 81.9%, and 56.1%, respectively.ConclusionsWe determined the prevalences of hyperuricemia and electrolyte abnormalities in Japanese patients with CKD using data from a nationwide cohort study.

Published
2020
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26. Prevalence of anemia in patients with chronic kidney disease in Japan: A nationwide, cross-sectional cohort study using data from the Japan Chronic Kidney Disease Database (J-CKD-DB).

Author

Tadashi Sofue, Naoki Nakagawa, Eiichiro Kanda, Hajime Nagasu, Kunihiro Matsushita, Masaomi Nangaku, Shoichi Maruyama, Takashi Wada, Yoshio Terada, Kunihiro Yamagata, Ichiei Narita, Motoko Yanagita, Hitoshi Sugiyama, Takashi Shigematsu, Takafumi Ito, Kouichi Tamura, Yoshitaka Isaka, Hirokazu Okada, Kazuhiko Tsuruya, Hitoshi Yokoyama, Naoki Nakashima, Hiromi Kataoka, Kazuhiko Ohe, Mihoko Okada, and Naoki Kashihara

Subjects
Medicine, Science
Abstract

BackgroundThe Japan Chronic Kidney Disease Database (J-CKD-DB) is a nationwide clinical database of patients with chronic kidney disease (CKD) based on electronic health records. The objective of this study was to assess the prevalence of anemia and the utilization rate of erythropoiesis-stimulating agents (ESAs) in Japanese patients with CKD.MethodsIn total, 31,082 adult outpatients with estimated glomerular filtration rates of 5-60 ml/min/1.73 m2 in seven university hospitals were included this analysis. The proportions of patients with CKD stages G3b, G4, and G5 were 23.5%, 7.6%, and 3.1%, respectively.ResultsThe mean (standard deviation) hemoglobin level of male patients was 13.6 (1.9) g/dl, which was significantly higher than the mean hemoglobin level of female patients (12.4 (1.6) g/dl). The mean (standard deviation) hemoglobin levels were 11.4 (2.1) g/dl in patients with CKD stage G4 and 11.2 (1.8) g/dl in patients with CKD stage G5. The prevalences of anemia were 40.1% in patients with CKD stage G4 and 60.3% in patients with CKD stage G5. Logistic regression analysis showed that diagnoses of CKD stage G3b (adjusted odds ratio [95% confidence interval]: 2.32 [2.09-2.58]), G4 (5.50 [4.80-6.31]), and G5 (9.75 [8.13-11.7]) were associated with increased prevalence of anemia. The utilization rates of ESAs were 7.9% in patients with CKD stage G4 and 22.4% in patients with CKD stage G5.ConclusionsWe determined the prevalence of anemia and utilization rate of ESAs in Japanese patients with CKD using data from a nationwide cohort study.

Published
2020
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27. The Japanese Clinical Practice Guideline for acute kidney injury 2016

Author

Kent Doi, Osamu Nishida, Takashi Shigematsu, Tomohito Sadahiro, Noritomo Itami, Kunitoshi Iseki, Yukio Yuzawa, Hirokazu Okada, Daisuke Koya, Hideyasu Kiyomoto, Yugo Shibagaki, Kenichi Matsuda, Akihiko Kato, Terumasa Hayashi, Tomonari Ogawa, Tatsuo Tsukamoto, Eisei Noiri, Shigeo Negi, Koichi Kamei, Hirotsugu Kitayama, Naoki Kashihara, Toshiki Moriyama, Yoshio Terada, and The Japanese Clinical Practice Guideline for Acute Kidney Injury 2016 Committee

Subjects
Acute kidney injury, Atrial natriuretic peptide, Biomarker, Blood purification, Long-term follow-up, Nafamostat mesilate, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Abstract Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention are necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search.

Published
2018
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28. Summary of the 2018 ISN Frontiers Meeting: Kidney Disease and Cardiovascular Disease

Author

Shinji Kume, Hajime Nagasu, Masaomi Nangaku, Akira Nishiyama, Hidetomo Nakamoto, and Naoki Kashihara

Subjects
Diseases of the genitourinary system. Urology, RC870-923
Abstract

International Society of Nephrology (ISN) Frontiers meetings build on the success of the ISN Nexus and Forefronts series by bringing together basic scientists, clinicians, and practitioners in a unique setting. This new event was organized to make more innovative science available to a global audience by removing regional barriers in accessing the latest knowledge. The first ISN Frontiers meeting was organized in partnership between the Japanese Society of Nephrology and the Japanese Society for Dialysis Therapy, which was held in Tokyo in February 2018. The meeting focused on the topic “Kidney Disease & Cardiovascular Disease,” which covered a broad range of scientific and clinical fields, including nephrology, cardiovascular diseases, dialysis, transplantation, chronic kidney disease (CKD)–mineral bone disease (MBD), diabetes, pediatric nephrology, nutrition, pharmacology, and nursing. A total of 1584 active physicians and scientists from 64 countries attended the meeting, and a number of leading physician scientists from different and related disciplines of clinical and basic research described and reviewed recent discoveries. This report summarizes the main highlights of the meeting lectures. Keywords: acute kidney injury, cardiovascular disease, chronic kidney disease, CKD-MBD, diabetes, dialysis, nutrition, nursing science, pediatric nephrology, pharmacology, transplantation

Published
2018
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29. Endothelial Dysfunction Accelerates Impairment of Mitochondrial Function in Ageing Kidneys via Inflammasome Activation

Author

Yoshihisa Wada, Reina Umeno, Hajime Nagasu, Megumi Kondo, Atsuyuki Tokuyama, Hiroyuki Kadoya, Kengo Kidokoro, Shun’ichiro Taniguchi, Masafumi Takahashi, Tamaki Sasaki, and Naoki Kashihara

Subjects
inflammasome, senescence-associated secretory phenotype, macrophages, mitochondria dysfunction, ASC-deficient mice, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Chronic kidney disease is a common problem in the elderly and is associated with increased mortality. We have reported on the role of nitric oxide, which is generated from endothelial nitric oxide synthase (eNOS), in the progression of aged kidneys. To elucidate the role of endothelial dysfunction and the lack of an eNOS-NO pathway in ageing kidneys, we conducted experiments using eNOS and ASC-deficient mice. C57B/6 J mice (wild type (WT)), eNOS knockout (eNOS KO), and ASC knockout (ASC KO) mice were used in the present study. Then, eNOS/ASC double-knockout (eNOS/ASC DKO) mice were generated by crossing eNOS KO and ASC KO mice. These mice were sacrificed at 17−19 months old. The Masson positive area and the KIM-1 positive area tended to increase in eNOS KO mice, compared with WT mice, but not eNOS/ASC DKO mice. The COX-positive area was significantly reduced in eNOS KO mice, compared with WT and eNOS/ASC DKO mice. To determine whether inflammasomes were activated in infiltrating macrophages, the double staining of IL-18 and F4/80 was performed. IL-18 and F4/80 were found to be co-localised in the tubulointerstitial areas. Inflammasomes play a pivotal role in inflammaging in ageing kidneys. Furthermore, inflammasome activation may accelerate cellular senescence via mitochondrial dysfunction. The importance of endothelial function as a regulatory mechanism suggests that protection of endothelial function may be a potential therapeutic target.

Published
2021
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30. Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice

Author

Yuji Sogawa, Hajime Nagasu, Shigeki Iwase, Chieko Ihoriya, Seiji Itano, Atsushi Uchida, Kengo Kidokoro, Shun’ichiro Taniguchi, Masafumi Takahashi, Minoru Satoh, Tamaki Sasaki, Takafumi Suzuki, Masayuki Yamamoto, Tiffany Horng, and Naoki Kashihara

Subjects
Medicine, Science
Abstract

Abstract Chronic inflammation can be a major driver of the failure of a variety of organs, including chronic kidney disease (CKD). The NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been shown to play a pivotal role in inflammation in a mouse kidney disease model. Nuclear factor erythroid 2-related factor 2 (Nrf2), the master transcription factor for anti-oxidant responses, has also been implicated in inflammasome activation under physiological conditions. However, the mechanism underlying inflammasome activation in CKD remains elusive. Here, we show that the loss of Nrf2 suppresses fibrosis and inflammation in a unilateral ureter obstruction (UUO) model of CKD in mice. We consistently observed decreased expression of inflammation-related genes NLRP3 and IL-1β in Nrf2-deficient kidneys after UUO. Increased infiltration of M1, but not M2, macrophages appears to mediate the suppression of UUO-induced CKD symptoms. Furthermore, we found that activation of the NLRP3 inflammasome is attenuated in Nrf2-deficient bone marrow–derived macrophages. These results demonstrate that Nrf2-related inflammasome activation can promote CKD symptoms via infiltration of M1 macrophages. Thus, we have identified the Nrf2 pathway as a promising therapeutic target for CKD.

Published
2017
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31. SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

Author

Kyoko Kawahara, Tomoyuki Mukai, Masanori Iseki, Akiko Nagasu, Hajime Nagasu, Takahiko Akagi, Shoko Tsuji, Sumie Hiramatsu-Asano, Yasuyoshi Ueki, Katsuhiko Ishihara, Naoki Kashihara, and Yoshitaka Morita

Subjects
Src homology 3 domain-binding protein 2, systemic lupus erythematosus, lupus mouse model, dendritic cells, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4−CD8− T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. Conclusions: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

Published
2021
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32. The eNOS-NO pathway attenuates kidney dysfunction via suppression of inflammasome activation in aldosterone-induced renal injury model mice.

Author

Yuji Sogawa, Hajime Nagasu, Seiji Itano, Kengo Kidokoro, Shun'ichiro Taniguchi, Masafumi Takahashi, Hiroyuki Kadoya, Minoru Satoh, Tamaki Sasaki, and Naoki Kashihara

Subjects
Medicine, Science
Abstract

Hypertension causes vascular complications, such as stroke, cardiovascular disease, and chronic kidney disease (CKD). The relationship between endothelial dysfunction and progression of kidney disease is well known. However, the relationship between the eNOS-NO pathway and chronic inflammation, which is a common pathway for the progression of kidney disease, remains unexplored. We performed in vivo experiments to determine the role of the eNOS-NO pathway by using eNOS-deficient mice in a hypertensive kidney disease model. All mice were unilateral nephrectomized (Nx). One week after Nx, the mice were randomly divided into two groups: the aldosterone infusion groups and the vehicle groups. All mice also received a 1% NaCl solution instead of drinking water. The aldosterone infusion groups were treated with hydralazine to correct blood pressure differences. After four weeks of drug administration, all mice were euthanized, and blood and kidney tissue samples were collected. In the results, NLRP3 inflammasome activation was elevated in the kidneys of the eNOS-deficient mice, and tubulointerstitial fibrosis was accelerated. Suppression of inflammasome activation by knocking out ASC prevented tubulointerstitial injury in the eNOS knockout mice, indicating that the eNOS-NO pathway is involved in the development of kidney dysfunction through acceleration of NLRP3 inflammasome in macrophages. We revealed that endothelial function, particularly the eNOS-NO pathway, attenuates the progression of renal tubulointerstitial injury via suppression of inflammasome activation. Clinically, patients who develop vascular endothelial dysfunction have lifestyle diseases, such as hypertension or diabetes, and are known to be at risk for CKD. Our study suggests that the eNOS-NO pathway could be a therapeutic target for the treatment of chronic kidney disease associated with endothelial dysfunction.

Published
2018
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33. Sh3bp2 Gain-Of-Function Mutation Ameliorates Lupus Phenotypes in B6.MRL-Faslpr Mice

Author

Akiko Nagasu, Tomoyuki Mukai, Masanori Iseki, Kyoko Kawahara, Shoko Tsuji, Hajime Nagasu, Yasuyoshi Ueki, Katsuhiko Ishihara, Naoki Kashihara, and Yoshitaka Morita

Subjects
SH3 domain–binding protein 2, systemic lupus erythematosus, murine lupus model, Fas, lpr mutation, double-negative T cells, anti-dsDNA antibody, tumor necrosis factor, macrophages, dendritic cells, Cytology, QH573-671
Abstract

SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein that is predominantly expressed in immune cells, and it regulates intracellular signaling. We had previously reported that a gain-of-function mutation in SH3BP2 exacerbates inflammation and bone loss in murine arthritis models. Here, we explored the involvement of SH3BP2 in a lupus model. Sh3bp2 gain-of-function (P416R knock-in; Sh3bp2KI/+) mice and lupus-prone B6.MRL-Faslpr mice were crossed to yield double-mutant (Sh3bp2KI/+Faslpr/lpr) mice. We monitored survival rates and proteinuria up to 48 weeks of age and assessed renal damage and serum anti-double-stranded DNA antibody levels. Additionally, we analyzed B and T cell subsets in lymphoid tissues by flow cytometry and determined the expression of apoptosis-related molecules in lymph nodes. Sh3bp2 gain-of-function mutation alleviated the poor survival rate, proteinuria, and glomerulosclerosis and significantly reduced serum anti-dsDNA antibody levels in Sh3bp2KI/+Faslpr/lpr mice. Additionally, B220+CD4−CD8− T cell population in lymph nodes was decreased in Sh3bp2KI/+Faslpr/lpr mice, which is possibly associated with the observed increase in cleaved caspase-3 and tumor necrosis factor levels. Sh3bp2 gain-of-function mutation ameliorated clinical and immunological phenotypes in lupus-prone mice. Our findings offer better insight into the unique immunopathological roles of SH3BP2 in autoimmune diseases.

Published
2019
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34. The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes: The PROLOGUE Randomized Controlled Trial.

Author

Jun-Ichi Oyama, Toyoaki Murohara, Masafumi Kitakaze, Tomoko Ishizu, Yasunori Sato, Kazuo Kitagawa, Haruo Kamiya, Masayoshi Ajioka, Masaharu Ishihara, Kazuoki Dai, Mamoru Nanasato, Masataka Sata, Koji Maemura, Hirofumi Tomiyama, Yukihito Higashi, Kohei Kaku, Hirotsugu Yamada, Munehide Matsuhisa, Kentaro Yamashita, Yasuko K Bando, Naoki Kashihara, Shinichiro Ueda, Teruo Inoue, Atsushi Tanaka, Koichi Node, and PROLOGUE Study Investigators

Subjects
Medicine
Abstract

BackgroundExperimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM).Methods and findingsWe used a multicenter PROBE (prospective, randomized, open label, blinded endpoint) design. Individuals aged ≥30 y with T2DM (6.2% ≤ HbA1c < 9.4%) were randomly allocated to receive either sitagliptin (25 to 100 mg/d) or conventional therapy. Carotid ultrasound was performed at participating medical centers, and all parameters were measured in a core laboratory. Of the 463 enrolled participants with T2DM, 442 were included in the primary analysis (sitagliptin group, 222; conventional therapy group, 220). Estimated mean (± standard error) common carotid artery IMT at 24 mo of follow-up in the sitagliptin and conventional therapy groups was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of -0.009 mm (97.2% CI -0.028 to 0.011, p = 0.309). HbA1c level at 24 mo was significantly lower with sitagliptin than with conventional therapy (6.56% ± 0.05% versus 6.72% ± 0.05%, p = 0.008; group mean difference -0.159, 95% CI -0.278 to -0.041). Episodes of serious hypoglycemia were recorded only in the conventional therapy group, and the rate of other adverse events was not different between the two groups. As it was not a placebo-controlled trial and carotid IMT was measured as a surrogate marker of atherosclerosis, there were some limitations of interpretation.ConclusionsIn the PROLOGUE study, there was no evidence that treatment with sitagliptin had an additional effect on the progression of carotid IMT in participants with T2DM beyond that achieved with conventional treatment.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry UMIN000004490.

Published
2016
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35. Current status of the rapid decline in renal function due to diabetes mellitus and its associated factors: analysis using the National Database of Health Checkups in Japan

Author

Makoto Fujii, Yuko Ohno, Asuka Ikeda, Kayo Godai, Yaya Li, Yuko Nakamura, Daisuke Yabe, Kazuyo Tsushita, Naoki Kashihara, Kei Kamide, and Mai Kabayama

Subjects
Physiology, Internal Medicine, Cardiology and Cardiovascular Medicine
Abstract

The increasing number of patients undergoing dialysis due to diabetes mellitus (DM) is causing serious economic problems, and its reduction is an urgent policy issue in developed countries, including Japan. We aimed to assess the association between the annual rapid decline in renal function and health checkup measures, including blood pressure, to identify health guidance targets for preventing diabetic nephropathy (DN) and diabetic kidney disease (DKD) among individuals in a medical checkup system (“Tokuteikenshin” program) in 2018. This longitudinal analysis included 3,673,829 individuals who participated in the “Tokuteikenshin” program in 2018, had hemoglobin A1c (HbA1c) levels ≥5.6%, were available for follow-up, and underwent estimated glomerular filtration rate (eGFR) evaluation. We estimated the incidence of the relative annual decrease in eGFR ≥10% per 1000 person-years and odds ratios to evaluate the rapid decline in renal function and determine health guidance goals and their role in preventing DN and DKD. Overall, 20.83% of patients with DM had a rapid decline in renal function within the observation period. A rapid decline in renal function was associated with high systolic blood pressure, poor or strict DM control, increased urinary protein excretion, and decreased blood hemoglobin levels. The incidence of rapid decline in renal function is higher in DM, and appropriate systolic blood pressure and glycemic control are important to prevent the progression to DN or DKD. Our findings will be useful for researchers, clinicians, and other public health care members in establishing effective health guidance and guidelines for CKD prevention.

Published
2023

38. Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in patients with diabetic kidney disease: design and baseline characteristics of the AYAME study

Author

Masaomi Nangaku, Hirotaka Takama, Tomohiro Ichikawa, Kazuya Mukai, Masahiro Kojima, Yusuke Suzuki, Hirotaka Watada, Takashi Wada, Kohjiro Ueki, Ichiei Narita, Naoki Kashihara, Takashi Kadowaki, Hiroki Hase, and Tadao Akizawa

Subjects
Transplantation, Nephrology
Abstract

Background Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD), but currently available treatments do not improve kidney function or prevent the initiation of dialysis/kidney replacement therapy. A previous study demonstrated that bardoxolone methyl improves the estimated glomerular filtration rate (eGFR), but the study was prematurely terminated because of an imbalance in heart failure between treatment groups. The subsequent phase 2 TSUBAKI study demonstrated no incidence of heart failure and an improved eGFR and GFR as determined by inulin clearance in DKD patients. Methods This randomized, double-blind, placebo-controlled multicentre phase 3 study was designed to assess the efficacy and safety of bardoxolone methyl in DKD patients with an eGFR ≥15.0– Results The mean age of the 1013 patients is 65.9 years, 21.5% are female, the mean eGFR is 37.84 ml/min/1.73 m2 and the median UACR is 351.80 mg/g. Conclusions Appropriate patients are enrolled in this study. This study will investigate the long-term efficacy and safety of bardoxolone methyl in DKD patients covering a wider range of eGFR (≥15.0–

Published
2022

39. Deep learning analysis of clinical course of primary nephrotic syndrome: Japan Nephrotic Syndrome Cohort Study (JNSCS)

Author

Tomonori Kimura, Ryohei Yamamoto, Mitsuaki Yoshino, Ryuichi Sakate, Enyu Imai, Shoichi Maruyama, Hitoshi Yokoyama, Hitoshi Sugiyama, Kosaku Nitta, Tatsuo Tsukamoto, Shunya Uchida, Asami Takeda, Toshinobu Sato, Takashi Wada, Hiroki Hayashi, Yasuhiro Akai, Megumu Fukunaga, Kazuhiko Tsuruya, Kosuke Masutani, Tsuneo Konta, Tatsuya Shoji, Takeyuki Hiramatsu, Shunsuke Goto, Hirofumi Tamai, Saori Nishio, Kojiro Nagai, Kunihiro Yamagata, Hideo Yasuda, Shizunori Ichida, Tomohiko Naruse, Tomoya Nishino, Hiroshi Sobajima, Toshiyuki Akahori, Takafumi Ito, Yoshio Terada, Ritsuko Katafuchi, Shouichi Fujimoto, Hirokazu Okada, Tetsushi Mimura, Satoshi Suzuki, Yosuke Saka, Tadashi Sofue, Kiyoki Kitagawa, Yoshiro Fujita, Makoto Mizutani, Naoki Kashihara, Hiroshi Sato, Ichiei Narita, and Yoshitaka Isaka

Subjects
Cohort Studies, Proteinuria, Nephrotic Syndrome, Deep Learning, Japan, Nephrology, Physiology, Creatinine, Physiology (medical), Humans, Hematuria
Abstract

Background Prognosis of nephrotic syndrome has been evaluated based on pathological diagnosis, whereas its clinical course is monitored using objective items and the treatment strategy is largely the same. We examined whether the entire natural history of nephrotic syndrome could be evaluated using objective common clinical items. Methods Machine learning clustering was performed on 205 cases from the Japan Nephrotic Syndrome Cohort Study, whose clinical parameters, serum creatinine, serum albumin, dipstick hematuria, and proteinuria were traceable after kidney biopsy at 5 measured points up to 2 years. The clinical patterns of time-series data were learned using long short-term memory (LSTM)-encoder–decoder architecture, an unsupervised machine learning classifier. Clinical clusters were defined as Gaussian mixture distributions in a two-dimensional scatter plot based on the highest log-likelihood. Results Time-series data of nephrotic syndrome were classified into four clusters. Patients in the fourth cluster showed the increase in serum creatinine in the later part of the follow-up period. Patients in both the third and fourth clusters were initially high in both hematuria and proteinuria, whereas a lack of decline in the urinary protein level preceded the worsening of kidney function in fourth cluster. The original diseases of fourth cluster included all the disease studied in this cohort. Conclusions Four kinds of clinical courses were identified in nephrotic syndrome. This classified clinical course may help objectively grasp the actual condition or treatment resistance of individual patients with nephrotic syndrome.

Published
2022

40. Dapagliflozin and Anemia in Patients with Chronic Kidney Disease

Author

Akihiko Koshino, Meir Schechter, Glenn M. Chertow, Priya Vart, Niels Jongs, Robert D. Toto, Peter Rossing, Ricardo Correa-Rotter, John J.V. McMurray, Jose Luis Górriz, Rey Isidto, Naoki Kashihara, Anna Maria Langkilde, David C. Wheeler, and Hiddo J.L. Heerspink

Published
2023

41. Chronic kidney disease and clinical outcomes in patients with COVID-19 in Japan

Author

Ryosuke Sato, Yasushi Matsuzawa, Hisao Ogawa, Kazuo Kimura, Nobuo Tsuboi, Takashi Yokoo, Hirokazu Okada, Masaaki Konishi, Jin Kirigaya, Kazuki Fukui, Kengo Tsukahara, Hiroyuki Shimizu, Keisuke Iwabuchi, Yu Yamada, Kenichiro Saka, Ichiro Takeuchi, Naoki Kashihara, and Kouichi Tamura

Subjects
Adult, SARS-CoV-2, Physiology, COVID-19, Middle Aged, Intensive Care Units, Proteinuria, Japan, Risk Factors, Nephrology, Physiology (medical), Humans, Hospital Mortality, Renal Insufficiency, Chronic, Aged, Retrospective Studies
Abstract

Identifying predictive factors for coronavirus disease 2019 (COVID-19) is crucial for risk stratification and intervention. Kidney dysfunction contributes to the severity of various infectious diseases. However, the association between on-admission kidney dysfunction and the clinical outcome in COVID-19 patients is unclear.This study was a multicenter retrospective observational cohort study of COVID-19 patients, diagnosed by polymerase chain reaction. We retrospectively analyzed 500 COVID-19 patients (mean age: 51 ± 19 years) admitted to eight hospitals in Japan. Kidney dysfunction was defined as a reduced estimated glomerular filtration rate ( 60 mL/min/1.73 mOverall, 171 (34.2%) patients presented with on-admission kidney dysfunction, and the primary composite outcome was observed in 60 (12.0%) patients. Patients with kidney dysfunction showed higher rates of in-hospital death (12.3 vs. 1.2%), mechanical ventilation (13.5 vs. 4.0%), and ICU admission (18.1 vs. 5.2%) than those without it. Categorical and multivariate regression analyses revealed that kidney dysfunction was substantially associated with the primary composite outcome. Thus, on-admission kidney dysfunction was common in COVID-19 patients. Furthermore, it correlated significantly and positively with COVID-19 severity and mortality.On-admission kidney dysfunction was associated with disease severity and poor short-term prognosis in patients with COVID-19. Thus, on-admission kidney dysfunction has the potential to stratify risks in COVID-19 patients.

Published
2022

43. Empagliflozin in Patients with Chronic Kidney Disease

Author

Herrington, William G, Staplin, Natalie, Wanner, Christoph, Green, Jennifer B, Hauske, Sibylle J, Emberson, Jonathan R, Preiss, David, Judge, Parminder, Mayne, Kaitlin J, Ng, Sarah Y A, Sammons, Emily, Zhu, Doreen, Hill, Michael, Stevens, Will, Wallendszus, Karl, Brenner, Susanne, Cheung, Alfred K, Liu, Zhi-Hong, Li, Jing, Hooi, Lai Seong, Liu, Wen, Kadowaki, Takashi, Nangaku, Masaomi, Levin, Adeera, Cherney, David, Maggioni, Aldo P, Pontremoli, Roberto, Deo, Rajat, Goto, Shinya, Rossello, Xavier, Tuttle, Katherine R, Steubl, Dominik, Petrini, Michaela, Massey, Dan, Eilbracht, Jens, Brueckmann, Martina, Landray, Martin J, Baigent, Colin, Haynes, Richard, The EMPA-KIDNEY Collaborative Group: Colin Baigent, Martin J Landray, Christoph Wanner, William G Herrington, Richard Haynes, Jennifer B Green, Sibylle J Hauske, Martina Brueckmann, Mark Hopley, Maximillian von-Eynatten, Jyothis George, Susanne Brenner, Alfred K Cheung, David Preiss, Zhi-Hong Liu, Jing Li, Laiseong Hooi, Wen Liu, Takashi Kadowaki, Masaomi Nangaku, Adeera Levin, David Cherney, Roberto Pontremoli, Aldo P Maggioni, Natalie Staplin, Jonathan Emberson, Stefan Hantel, Shinya Goto, Rajat Deo, Katherine R Tuttle, Michael Hill, Parminder Judge, Kaitlin J Mayne, Sarah Y A Ng, Xavier Rossello, Emily Sammons, Doreen Zhu, Peter Sandercock, Rudolf Bilous, Charles Herzog, Paul Whelton, Janet Wittes, Derrick Bennett, Patricia Achiri, Chrissie Ambrose, Cristina Badin, Jill Barton, Richard Brown, Andy Burke, Sebastian Butler, Rejive Dayanandan, Pia Donaldson, Robert Dykas, Lucy Fletcher, Kate Frederick, Hannah Kingston, Mo Gray, Emily Harding, Akiko Hashimoto, Lyn Howie, Susan Hurley, Ryonfa Lee, Nik Luker, Kevin Murphy, Mariko Nakahara, John Nolan, Michelle Nunn, Sorcha Mulligan, Akiko Omata, Sandra Pickworth, YanRu Qiao, Shraddha Shah, Karen Taylor, Alison Timadjer, Monique Willett, Liz Wincott, Qin Yan, Hui Yu, Louise Bowman, Fang Chen, Robert Clarke, Michelle Goonasekera, Waseem Karsan, Marion Mafham, Christina Reith, Mohammed Zayed, Ritva Ellison, Rowan Moys, Will Stevens, Kevin Verdel, Karl Wallendszus, Chris Bowler, Anna Brewer, Andy Measor, Guanguo Cui, Charles Daniels, Angela Field, Bob Goodenough, Ashley Lawson, Youcef Mostefai, Dheeptha Radhakrishnan, Samee Syed, Shuang Xia, Ruth Adewuyi-Dalton, Thomas Arnold, Anne-Marie Beneat, Anoushka Bhatt, Chloe Bird, Andrew Breach, Laura Brown, Mark Caple, Tatyana Chavagnon, Karen Chung, Sarah Clark, Luminita Condurache, Katarzyna Eichstadt, Marta Espino Obrero, Scarlett Forest, Helen French, Nick Goodwin, Andrew Gordon, Joanne Gordon, Cat Guest, Tina Harding, Michal Hozak, Matthew Lacey, David MacLean, Louise Messinger, Stewart Moffat, Martin Radley, Claire Shenton, Sarah Tipper, Jon Tyler, Lesley Weaving, James Wheeler, Elissa Williams, Tim Williams, Hamish Woodhouse, Angela Chamberlain, Jo Chambers, Joanne Davies, Denise Donaldson, Pati Faria-Shayler, Denise Fleming-Brown, Jennifer Ingell, Carol Knott, Anna Liew, Helen Lochhead, Juliette Meek, Isabel Rodriguez-Bachiller, Andrea Wilson, Patrick Zettergren, Rach AitSadi, Ian Barton, Alex Baxter, Yonghong Bu, Lukasz Danel, Sonja Grotjahn, Rijo Kurien, Michael Lay, Archie Maskill, Aleksandra Murawska, Rachel Raff, Allen Young, Rebecca Sardell, Vladimir Cejka, Marcela Fajardo-Moser, Christian Hartner, Doris Poehler, Janina Renner, Franziska Scheidemantel, Miya Bryant, Anita Hepditch, Cassandra Johnson, Erin Latore, Yolanda Miller, Lauren Price, Merilee Whalen, Ashleigh Wheeler, Jenny Ingell, Yu An, Yinghua Chen, Peiling Chen, Hao Dai, Hong Du, Fang Feng, Qing Guo, Libo Hou, Wuhanbilige Hundei, Binbin Jin, Yan Li, Jiamin Liu, Xia Song, Yanping Wang, Yanwu Yu, Ning Zhang, Lingshan Zhao, Hui Zhong, Cheng Beng Goh, Ye Mun Low, Soon Yi Sor, Farah Hanis Zulkipli, Sarojini Sivanandam, Natsuki Arai, Ai Fukasawa, Mizue Furukawa, Keisuke Habuki, Shoko Hayashi, Wakako Isari, Saki Kanegae, Maria Kawai, Reiki Kobayashi, Takako Kuramae, Chika Kuribayashi, Sawako Maeno, Satoshi Masumoto, Tomoko Morisaki, Minoru Oda, Kazue Sawada, Kenta Sugamori, Ayana Tatsuzawa, Aiko Tomita, Kazuyuki Yuasa, Hiroko Inazawa, Amanda Axler, Kerri Gallo, Ester Baldini, Barbara Bartolomei Mecatti, Francesca Bianchini, Martina Ceseri, Laura Cipressa, Gianna Fabbri, Andrea Lorimer, Donata Lucci, Sharang Ghavampour, Anja Knoppe, Hans Schmidt-Gurtler, Hubert Dumann, Sybille Merscher, Margret Patecki, Georg Rainer Schlieper, Anke Torp, Bianca Weber, Maja Zietz, Bernd Hohenstein, Urs Benck, Diliana Draganova, Thomas Weinreich, Lothar Wolf, Jasmine Gaidu, Hanna Reiner, Mandy Visnjic, Daniel Steffl, Marie Breitenfeldt, Annette Kraemer-Guth, Christine Braun, Simone Hagge, Michael Schomig, Stephan Matthias, Dominik Stoffler, Beate Schumacher, Thomas Sitter, Louise Fuessl, Julia Krappe, Jerome Loutan, Volker Vielhauer, Luciano Andriaccio, Magdalena Maurer, Bernhard Winkelmann, Martin Dursch, Linda Seifert, Linda Tenbusch, Julia Weinmann-Menke, Simone Boedecker, Wiebke Kaluza-Schilling, Daniel Kraus, Carina Krieger, Margit Schmude, Anne Schreiber, Ewelina Eckrich, Diethelm Tschope, Abdulwahab Arbi, Young Lee-Barkey, Bernd Stratmann, Natalie Prib, Sina Rolfsmeier, Irina Schneider, Lars Rump, Johannes Stegbauer, Christine Pötz, Mara Schemmelmann, Claudia Schmidt, Michael Koch, Sendogan Aker, Annika Küpper, Manuela Martin, Thiemo Pfab, Christian Albert, Michael Haase, Barbara Zander, Claudia Schneider-Danwitz, Wolfgang Seeger, Wolf-Adam Seeger, Britta Zemann, Christoph Stellbrink, Kristin Marx, Ekaterina Stellbrink, Britta Brettschneider, Stephanie Watson, Marion Iselt, Gerhard Klausmann, Inga-Nadine Kummer, Auguste Kutschat, Simone Streitenberger, Matthias Girndt, Silke Markau, Ina Girakossyan, Claudia Hanf, Joachim Beige, Ralph Wendt, Ulrike Schmidt, Andreas Schneider, Roland Veelken, Claudia Donhauser, Luis Becker, Nexhat Miftari, Ricarda Wolfling, Sarah Morlok, Christian Hugo, Alexander Paliege, Jens Passauer, Julian Stumpf, Annegret Fleischer, Kerstin Haaser, Bernhard Kraemer, Jan Jochims, Bernd Kruger, Claudia Foellinger, Anastassiya Reisler, Frank Strutz, Stefan Haack, Ursula Hohenstatt, Martin Busch, Konstantin Herfurth, Gunter Wolf, Rainer Paul, Hermann Haller, Jessica Kaufeld, Jan Menne, Elisabeth Bahlmann-Kroll, Angela Bergner, Horst Weihprecht, Aydin Er, Florian Sonntag, Elif Turan, Michael Wittmann, Franziska Klauser, Eva Voigt, Volker Schettler, Egbert Schulz, Madlen Rohnstock, Elke Schettler, Bernd Schroppel, Rene van Erp, Martin Kachele, Ulla Ludwig, Lena Schulte-Kemna, Waltraud Kmietschak, Elke Preiss, Martina Ruocco, Gunnar Heine, Martin Brzoska, Sebastian Gabel, Christina Büttner, Asma Sabarai, Bernhard Banas, Tobias Bergler, Yvonne Ehrl, Franz Putz, Antonia Schuster, Stefanie Kuhn, Torsten Schramm, Stefan Degenhardt, Gerhard Schmidt, Lea Weiland, Ulrike Giebeln-Hudnell, Jan Kielstein, Gabriele Eden, Brigitte Fuchs, Gina Morig, Manuela Winkler, Harald Darius, Charalampos Kriatselis, Carl-Philipp Roesch, Astrid Maselli, Dominik Alscher, Markus Ketteler, Moritz Schanz, Severin Schricker, Bianka Rettenmaier, Andrea Schwab, Pablo Pergola, Irene Leal, Melissa Cagle, Anna Romo, Anthony Torres, Sucharit Joshi, Kulli Barrett, Alexis Africano, Vicki Dodds, Dorleena Gowen, Ashlee Morris, Juan Fernandez, Guillermo Jimenez, Ricardo Viera, Kendaling Bruce, Ryan Barrios, Maylin Garcia, Kerelyn Garcia, Iradis Leal, David Tietjen, David Bains, Carlo Castillo, Genielle Brewer, Justin Davis, Natalie Freking, Brittany Golson, Sally Ham, Jesslyn Roesch, Pusadee Suchinda, Shameem Beigh, Usah Lilavivat, Joyce Bilton, Kim Bocchicchia, Jeffrey Turner, Neera Dahl, Aldo Peixoto, Yasemin Kavak, Lauren Liberti, Hari Nair, Nicolas Page, Stephanie Rosenberg, Kathryn Simmons, Tamara Isakova, Rebecca Frazier, Rupal Mehta, Anand Srivastava, Patrick Fox, Jonathan Hecktman, Alexander Hodakowski, Carlos Martinez, Rachel Phillips, Alexis Stevenson, Reem Mustafa, Kyle Jansson, Cassandra Kimber, Jason Stubbs, Ahmad Tuffaha, Sri Yarlagadda, Debbie Griffin, Elisabeth Laundy, Zhuo Tang, Radica Alicic, Ann Cooper, Lisa Davis, Ashwini Gore, Rebecca Goldfaden, Leslie Harvill, Lisa Hichkad, Barry Johns, Thomas Jones, Kayla Merritt, Jennifer Sheldon, Jennifer Stanfield, Lindsay Alexander, Kaitlyn Preston, Lindsey Wood, Rajesh Pradhan, Roger DeRaad, Kelli McIntosh, Louis Raymond, Michael Shepperd, Susan McLaughlin, Mary Seifert, Andrew Shepherd, Joseph Aiello, William Durham, Laurie Loudermilk, John Manley, Sabrina Burnette, Stephanie Evans, Tara Johnson, Lance Sloan, Judy Ann Acosta, Stacy Gillham, Katia Sloan, SueAnn Squyres, Michael Rocco, Amret Hawfield, Ben Bagwell, Lauren Richmond, Joseph Soufer, Subha Clarke, Amanda Aliu, Kristine Calabrese, Amanda Davis, Veronica Poma, Tracy Spinola, James Magee, Ricardo Silva, Rushab Choksi, Lorraine Dajani, John Evans, Anil George, Prasanth Krish, Gerard Martins, Mae Sheikh-Ali, David Sutton, Freda Driver, Abraham Hanburry, Laura Hume, Amber Hurst, Matthew Taddeo, Marla Turner, Veronica Yousif, Srinivasan Beddhu, Laith Al-Rabadi, Nikita Abraham, Amalia Caamano, Judy Carle, Victoria Gonce, Kaitlyn Staylor, Na Zhou, Shweta Bansal, Manoj Bhattarai, Kumar Sharma, Subrata Debnath, Aliseiya Garza, Chakradhar Velagapudi, Sergio Rovner, Javier Almeida, Pablo Casares, Verlaine Stewart-Ray, Rene Almaraz, Renata Dayrell, Ana Moncada, Ricardo Pulido, Roxana Rodriquez, Wasim Deeb, Kathryn DeGoursey, Rodel Gloria, Trevor Greene, Robert Miller, Edward Pereira, Miguel Roura, Debbie Domingo, Sasha Dorestin, William Hodge, Cathy Jackson, Deborah Lund, Katrina Taylor, Kenneth Boren, Brittany Cleveland, Sandra Gaiser, Mandeep Sahani, Logan Aldrich, Exodus Edmerson, Edmond Limon, Cole Valletta, Patricia Vasquez, Christopher Provenzano, Navkiranjot Brar, Heather Henderson, Bellovich Keith, Qur Khai, Quresh Khairullah, Gail Makos, Joel Topf, Sherry Gasko, Rosemarie Henschel, Kaitlin Knapp, Teresa Kozlowski, Paula LaFleur, Ashwathy Varughese, Hui Xue, Patricia Wu, Olga Arechiga, Shan Darbeau, Michael Fechter, Stephanie Martinez, Lenita Hanson, Nyla Cooper, Arelis Madera, Jay Cadorna, Rita Sheridan, Helen Sparks, Bradley Eilerman, Susanne Bodine, Wael Eid, Rebecca Flora, Amber Avery, Cashmere Hardy, Mihaela Biscoveanu, Steven Nagelberg, Tracey Cummins, Frederic Rahbari-Oskoui, Anju Oommen, Zohreh Forghani, Stacie Hitchcock, Darya Hosein, Diane Watkins, Minesh Patel, Anthony Lambert, Elizabeth Newman, Autumn Wood, Tammy Ross, Stephany Topping, Jeffrey Mulhern, Lorna Murphy, Ann Vasseur, Gregory Greenwood, Alexander Hadley, Denise Laurienti, Christopher Marshall, Nicholas McLean, Scott Satko, Brandy Caudill, Jacob Maris, Janice Rogers, Cindy Vanhoy, George Thomas, Georges Nakhoul, John O'Toole, Jonathan Taliercio, Leslie Cooperman, Marina Markovic, Barbara Tucky, Devasmita Dev, Alia Hasan, Hima Yalamanchili, Namita Jain, Lesley McNeil, Eric Wines, Jean Park, Adline Ghazi, Mia Hamm, Tejas Patel, Amy Mottl, Emily Chang, Vimal Derebail, Emmie Cole, Anne Froment, Sara Kelley, Jordan Osmond Foster, Vahid Mahabadi, Golriz Jafari, Anita Kamarzarian, Wendy Arriaga, Daisy Arteaga, Rosario Machicado, Genesis Naverrete, Prashant Kumar, Imran Nazeer, Karina Urquia, Tammi Glider, Vickie Jones, Savannah Rucker, Jennifer Wiley, Rahul Pandey, Jesus Arroyo, Harish Pariani, Mohammad Ahmad, Shahin Mozaffari, Erika Perez, Matthew Budoff, Sion Roy, Divya Birudaraju, Ahmed Ghanem, Sajad Hamal, Stephen Aronoff, Elisa Joye Petr, Richard Sachson, Jaime Wiebel, Sana Akram, Laurie Jones, Curtis Knight, Maurie Tarlac, Shahbaz Ahmed, Harold Szerlip, Akinwande Akinfolarin, Ankit Mehta, Shana Camp, Cindy Castro, Zanaida Cooper, Jessica Terry, Ahmed Awad, Bhavya Kothapalli, Ryan Lustig, Serine Alfaress, Hyder Jasim, Mary Parrigon, Dennis Karounos, Sadiq Ahmed, Maggie Berry, Ruth Oremus, Carlos Hernandez-Cassis, Elias Ugwu, Nazia Junejo, Nancy Suazo, Mark Segal, Amir Kazory, Sherry Brown, Tristan Daniels, Sofia Dayi, Renee Hogan, Kathy McCray, Jennifer Stickley, Mahboob Rahman, Mirela Dobre, Lavinia Negrea, Aparna Padiyar, Nishigandha Pradhan, Arash Rashidi, Nagaraju Sarabu, Vicki Donley, Tricia Young, Godson Oguchi, Judepatricks Onyema, Kahla Damianik, Jack Dienes, Judith Plummer-Morgan, Marilyn Roman, Mauver Skipper, Stacey-Ann Villaruel, Krystle Williams, Danny Sugimoto, Jeffrey Dugas, Ismeal Ahmed, Jamie Bhairoo, Dolores Rijos, Huzaifa Salim, Madita Gavrila, Kathryn Lafferty, Ria Rabara, Sally Ruse, Maria Weetman, James Bushnell, Albert Power, Alison Jenkins, Stefanie Jones, Amanda Scott, Cath Byrne, Mark Jesky, Alison Cowley, Emma McHaffie, Holly Waterfall, Jo Taylor, Laura Bough, Thomas Phillips, Barbara Winter-Goodwin, Sui Phin Kon, Iain MacDougall, Eirini Lioudaki, Sapna Shah, Claire Sharpe, Francisco Aguilar, Abegail Hernandez Pena, Conception Pugay, Amelia Te, Hugh Finn, Wasim Hanif, Samiul Mostafa, Alice Aitken, Katharine Draxlbauer, Evelina Grobovaite, Jennifer Kearney, Theresa McCarthy, Giorgio Gentile, Duncan Browne, Palanichamy Chellamuthu, Tabinda Dugal, Terri Chant, Laura Jones, Emily Laity, Megan Miners, James Muir, Elizabeth Swanson, Andrew Frankel, James Tomlinson, Marlon Alegata, Rashid Almasarwah, Anthoula Apostolidi, Maria Vourvou, Thomas Walters, Maarten Taal, Hari Dukka, Nitin Kolhe, Carly McDonald, Kelly White, Shiva Ugni, Smita Gunda, Rotimi Oluyombo, Vicki Brindle, Ping Coutts, Tracy Fuller, Evelyn Nadar, Suresh Ramadoss, Nichola Motherwell, Susannah Pajak, Louise Tonks, Sunil Bhandari, Richard Bodington, Adil Hazara, Dominic Fellowes, Christopher Wong, Christopher Goldsmith, Sherald Barnes, Ann Bennett, Claire Burston, Samantha Hope, Nicola Hunt, Lini Kurian, Richard Fish, Daniela Farrugia, Judy Lee, Emma Sadler, Hannah Turner, Christopher Hill, Henry Brown, Agnes Masengu, Peter Maxwell, Nina Bleakley, Hugh Murtagh, William Petchey, Vivian Yiu, Joanne Kellett, Angharad Williams, Helen Clarke, Victoria Carnall, Sarah Benyon, Caroline Blake, Stephanie Estcourt, Jane Piper, Neal Morgan, Carolyn Hutchinson, Teresa McKinley, Alastair Woodman, Judi Graham, Niall Leonard, John Smyth, Vicki Adell, Samantha Hagan, Ben Caplin, Amin Oomatia, Eleanor Damian, Toluleyi Sobande, Tim Doulton, Michael Delaney, Mahmoud Montasser, Jenny Hansen, David Loader, Angela Moon, Frances Morris, Smeeta Sinha, Chukwuma Chukwu, Amy Hudson, Diane Campbell, Melanie Kershaw, Stephanie Whittaker, Ayesha Irtiza-Ali, Farid Ghalli, Heba Nosseir, Allison Leslie, Kate Trivedi, Donald Fraser, Mohammad Alhadj Ali, Sian Griffin, Farah Latif, Justyna Witczak, Alexa Wonnacott, Lynda Jeffers, Yvette Webley, Paul Phelan, Eve Miller-Hodges, Ailsa Geddes, Margaret Glenwright, Amy Hunter, Thomas Pickett, Jim Moriarty, Linda Hill, Amanda Tyler, Waqar Ayub, Gail Evans, Sue Hewins, Davina Hewitt, Kerry Read, Samira Bell, Leanne Cosgrove, Rachel Craik, Shona Murray, Nitin Bhandary, Holly Coles, Rashmi Easow, Maya Joseph, Arif Khwaja, Yvonne Jackson, Angeline Mbuyisa, Rachel Sellars, Nihil Chitalia, Cynthia Mohandas, Anca Gherman, Charlotte Kamundi, Olumide Olufuwa, Kieran McCafferty, Adedolapo Adeleke, Cara Healy, Damini Jeyarajah, Edward Kinsella-Perks, Richard Smith, Brian Camilleri, Carol Buckman, Jenny Finch, Vanessa Rivers, Andrew Connor, Sheila Carr, Lisa Shainberg, Andrew Lewington, Richard Baker, Suzannah Dorey, Kay Tobin, Rosalyn Wheatley, Debasish Banerjee, Richard Hull, Sharirose Abat, Riny Paul, Mahzuz Karim, Zay Htet, Saad Tufail, Ravi Varma, Karen Convery, Deirdre Fottrell-Gould, Lisa Hudig, Emily Tropman, Thahir Abdul-Samad, Anne Grace, Marie Phipps, Rebecca Suckling, Subash Somalanka, Bhrigu Sood, Pauline Swift, Sarah Acheampong, Kwame Ansu, Martia Augustin, Anna Sampson, Lynn Vinall, Kim Wren, Shamila Wanninayake, Nicholas Wooding, Heather Edwards, Lydia Owen, Stephanie Bolton, Marion Carson, Michael Matthews, Nigel Brunskill, Jorge Jesus-Silva, Alex Howson, Mary Quashie-Akponeware, Hilary Tindall, Chidambaram Nethaji, Helen Eldon, Rajan Patel, Patrick Mark, Alastair Rankin, Michael Sullivan, Kirsty Forsyth, Rowan McDougall, Tanaji Dasgupta, Louisa Davies, Maggie Ryder, Philip Grimmer, Clare Macdonald, Mary Webster, Newcastle Newcastle, Timothy Ellam, Edwin Wong, Christine Meshykhi, Andrea Webster, Peter Wilson, Enric Vilar, Jocelyn Berdeprado, Eunice Doctolero, Lily Wilkinson, Frank McCarroll, Hesham Ammar, Ying Kuan, Conor Moran, Girish Shivashankar, Ryan Campbell, Deborah Glowski, Paula McDermott, Amar Ali, Zuber Patel, Christine Bond, Gillian Whalley, Haitao Zhang, Liu Yang, Lihua Zhang, Tingting Kan, Ling Zhu, Jinghong Zhao, Weiping Hou, Jing Wu, Hong Cheng, Weijing Bian, Zhirui Zhao, Fengmin Shao, Huixia Cao, Xiaojing Jiao, Peiyuan Niu, Jianying Niu, Yu Chen, Lihong Zhang, Shenglang Zhu, Haiyan Lin, Shaopeng Yao, Jiehui Chen, Ying Jiang, Ying Hu, Huaying Xiao, Fuye Yang, Xinzhou Zhang, Baochun Guo, Qiu Jin, Lixia Liu, Xiangcheng Xiao, Yanyun Xie, Ting Meng, Chuanwen Xu, Jie Huang, Yanmei Xu, Weixin Kong, Xiaoliang Wang, Qianpan Liu, Xueying Wang, Ming Gao, Xiumei Hu, Ying Lu, Li Wang, Kun Peng, Wei Wang, Qiuhong Gong, Jianfang Cai, Xiaojue Li, Xuejiao Liu, Shuhan Zhou, Hong Liu, Yao Weng, Shuai Tang, Yao Yao, Shi Zhao, Chen Cheng, Wei Wei, Na Li, Sadanah Aqashiah Mazlan, Alia Zubaidah Bahtar, Elliyyin Katiman, Noraini Othman, Lily Mushahar, Nurdiana Mazlan, Nur Sharafina Safiee, Sarasa Ramasamy, Hin Seng Wong, Hajar Ahmad Rosdi, Esther Zhao Zhi Tan, Ju Fan Tay, Kok Seng Teng, Hasnah Yahaya, Wen Jiun Liu, Lik Wee Ee, Kenneth Kay Leong Khoo, Yuana Mohd Yusoff, Fariz Safhan Mohamad Nor, Mohd Kamil Ahmad, Mohd Ramli Seman, Clare Hui Hong Tan, Laura Lui Sian Ngu, Jaime Yoke May Chan, Javelin Peji, Chek Loong Loh, Yee Yan Lee, Sridhar Ramanaidu, Kah Mean Thong, Yik Hong Wong, Suria Junus, Chen Hua Ching, Mohammad Faisal Asmee, Ku Ruziana Ku Md Razi, Chun Leong Low, Christopher Sze Bing Sim, Zhang Duan Tham, Noor Kamila Abdullah, Tai Meng Chen, Yong Chieh Chan, Eason Chang, Huan Yean Kang, Kai Quan Lee, Sue Ann Lee, Aik Kheng Lee, Jeevika Vinathan, Rizna Abdul 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Matthew, Turner, Marla, Yousif, Veronica, Beddhu, Srinivasan, Al-Rabadi, Laith, Abraham, Nikita, Caamano, Amalia, Carle, Judy, Gonce, Victoria, Staylor, Kaitlyn, Zhou, Na, Bansal, Shweta, Bhattarai, Manoj, Sharma, Kumar, Debnath, Subrata, Garza, Aliseiya, Velagapudi, Chakradhar, Rovner, Sergio, Almeida, Javier, Casares, Pablo, Stewart-Ray, Verlaine, Almaraz, Rene, Dayrell, Renata, Moncada, Ana, Pulido, Ricardo, Rodriquez, Roxana, Deeb, Wasim, Degoursey, Kathryn, Gloria, Rodel, Greene, Trevor, Miller, Robert, Pereira, Edward, Roura, Miguel, Domingo, Debbie, Dorestin, Sasha, Hodge, William, Jackson, Cathy, Lund, Deborah, Taylor, Katrina, Boren, Kenneth, Cleveland, Brittany, Gaiser, Sandra, Sahani, Mandeep, Aldrich, Logan, Edmerson, Exodu, Limon, Edmond, Valletta, Cole, Vasquez, Patricia, Provenzano, Christopher, Brar, Navkiranjot, Henderson, Heather, Keith, Bellovich, Khai, Qur, Khairullah, Quresh, Makos, Gail, Topf, Joel, Gasko, Sherry, Henschel, Rosemarie, Knapp, Kaitlin, Kozlowski, Teresa, Lafleur, Paula, Varughese, Ashwathy, Xue, Hui, Wu, Patricia, Arechiga, Olga, Darbeau, Shan, Fechter, Michael, Martinez, Stephanie, Hanson, Lenita, Cooper, Nyla, Madera, Areli, Cadorna, Jay, Sheridan, Rita, Sparks, Helen, Eilerman, Bradley, Bodine, Susanne, Eid, Wael, Flora, Rebecca, Avery, Amber, Hardy, Cashmere, Biscoveanu, Mihaela, Nagelberg, Steven, Cummins, Tracey, Rahbari-Oskoui, Frederic, Oommen, Anju, Forghani, Zohreh, Hitchcock, Stacie, Hosein, Darya, Watkins, Diane, Patel, Minesh, Lambert, Anthony, Newman, Elizabeth, Wood, Autumn, Ross, Tammy, Topping, Stephany, Mulhern, Jeffrey, Murphy, Lorna, Vasseur, Ann, Greenwood, Gregory, Hadley, Alexander, Laurienti, Denise, Marshall, Christopher, Mclean, Nichola, Satko, Scott, Caudill, Brandy, Maris, Jacob, Rogers, Janice, Vanhoy, Cindy, Thomas, George, Nakhoul, George, O'Toole, John, Taliercio, Jonathan, Cooperman, Leslie, Markovic, Marina, Tucky, Barbara, Dev, Devasmita, Hasan, Alia, Yalamanchili, Hima, Jain, Namita, Mcneil, Lesley, Wines, Eric, Park, Jean, Ghazi, Adline, Hamm, Mia, Patel, Teja, Mottl, Amy, Chang, Emily, Derebail, Vimal, Cole, Emmie, Froment, Anne, Kelley, Sara, Osmond Foster, Jordan, Mahabadi, Vahid, Jafari, Golriz, Kamarzarian, Anita, Arriaga, Wendy, Arteaga, Daisy, Machicado, Rosario, Naverrete, Genesi, Kumar, Prashant, Nazeer, Imran, Urquia, Karina, Glider, Tammi, Jones, Vickie, Rucker, Savannah, Wiley, Jennifer, Pandey, Rahul, Arroyo, Jesu, Pariani, Harish, Ahmad, Mohammad, Mozaffari, Shahin, Perez, Erika, Budoff, Matthew, Roy, Sion, Birudaraju, Divya, Ghanem, Ahmed, Hamal, Sajad, Aronoff, Stephen, Joye Petr, Elisa, Sachson, Richard, Wiebel, Jaime, Akram, Sana, Jones, Laurie, Knight, Curti, Tarlac, Maurie, Ahmed, Shahbaz, Szerlip, Harold, Akinfolarin, Akinwande, Mehta, Ankit, Camp, Shana, Castro, Cindy, Cooper, Zanaida, Terry, Jessica, Awad, Ahmed, Kothapalli, Bhavya, Lustig, Ryan, Alfaress, Serine, Jasim, Hyder, Parrigon, Mary, Karounos, Denni, Ahmed, Sadiq, Berry, Maggie, Oremus, 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Wen, Wee Ee, Lik, Kay Leong Khoo, Kenneth, Mohd Yusoff, Yuana, Safhan Mohamad Nor, Fariz, Kamil Ahmad, Mohd, Ramli Seman, Mohd, Hui Hong Tan, Clare, Lui Sian Ngu, Laura, Yoke May Chan, Jaime, Peji, Javelin, Loong Loh, Chek, Yan Lee, Yee, Ramanaidu, Sridhar, Mean Thong, Kah, Hong Wong, Yik, Junus, Suria, Hua Ching, Chen, Faisal Asmee, Mohammad, Ruziana Ku Md Razi, Ku, Leong Low, Chun, Sze Bing Sim, Christopher, Duan Tham, Zhang, Kamila Abdullah, Noor, Meng Chen, Tai, Chieh Chan, Yong, Chang, Eason, Yean Kang, Huan, Quan Lee, Kai, Ann Lee, Sue, Kheng Lee, Aik, Vinathan, Jeevika, Abdul Cader, Rizna, Mustafar, Ruslinda, Kamaruzaman, Lydia, Mohd, Rozita, Ismail, Rahimah, Men Leong, Chong, Koon Low, Chee, Wei Wong, Liang, Adnan, Norlezah, Ibrahim, Sabariah, Zaimi Abdul Wahab, Mohamad, Bavanandan, Sunita, Shen Lim, Yik, Hazlina Wan Mohamad, Wan, Munirah Jaafar, Siti, Ashykeen Mohd Fauzi, Nur, Sudin, Aziee, Kun Lim, Soo, Chung Gan, Chye, Hing, Albert, Ahmad Faizal Alaidin Razali, Wan, Fong Liew, Yew, Bao Tyng Chan, Chelsia, Chih Cheng, Mei, Chen Ong, Yu, Meng Ong, Loke, Amalina Mohamed Affandi, Farah, Rahmat, Korina, Chai Peng, Ban, Amat, Masayu, Hadafi Ahmad, Nuzaimin, Yee Mah, Doo, Loon Tye, Yi, Azhari, Zaid, Nabilah Mohamad Zaini, Siti, Aidil Musa, Mohd, Ahmad Miswan, Norazinizah, Ramli, Rafizanur, Aziah Ahmad, Nor, Leong Goh, Bak, Izah Ahmad, Nurul, Huda Ibrahim, Fairol, Jian Ng, Tze, Shanmuganathan, Malini, Lian Tay, Li, Harun, Zaiha, Ramli, Salmi, 'Ain Yusof, Nurul, Abd Rahman, Rossenizal, Iqbal Abdul Hafidz, Muhammad, Hidayati Mohd Sharif, Nur, Yasmoon Awang, Irda, Nakashima, Eitaro, Imamine, Rui, Minatoguchi, Makiko, Miura, Yukari, Nakaoka, Miduki, Suzuki, Yoshiki, Yoshikawa, Hitomi, Shin, Koki, Fujita, Kanae, Iwasa, Misuzu, Sasajima, Haruka, Sato, Airi, Hamamoto, Yoshiyuki, Fujita, Yuki, Haraguchi, Takuya, Hyo, Takanori, Izumi, Kiyohiro, Komiya, Toshiyuki, Kubota, Sodai, Kurose, Takeshi, Kuwata, Hitoshi, Nakatani, Susumu, Oishi, Kaori, Okamoto, Saki, Okamura, Kaori, Takeoka, Jun, Tanaka, Nagaaki, Tanigaki, Katsuya, Toda, Naohiro, Watanabe, Koin, Komori, Hiromi, Kumuji, Rika, Takesada, Asako, Tanaka, Aya, Maruyama, Shoichi, Hasegawa, Tomonori, Ishiguro, Akiko, Ishimoto, Takuji, Ito, Kazuhiro, Kamimura, Yutaka, Kato, Noritoshi, Kato, Sawako, Kojima, Hiroshi, Kosugi, Tomoki, Maeda, Kayaho, Mizuno, Masasi, Saito, Shoji, Sato, Hitomi, Sato, Yuka, Suzuki, Yasuhiro, Tanaka, Akihito, Yasuda, Yoshinari, Hasegawa, Fujiko, Hayashi, Maiko, Higashi, Shizuka, Shimamura, Kaho, Sumi, Momoko, Tajima, Kazuki, Unekawa, Chimaki, Wakayama, Kana, Wakita, Yukiko, Otani, Takatoshi, Imai, Ayako, Kawashima, Sayaka, Kogure, Eri, Sato, Tomoe, Takezawa, Misato, Yoshida, Shinya, Araki, Hideo, Katsuda, Yuko, Konishi, Masahiro, Matsunaga, Takahiro, Oe, Masashi, Ogane, Kunihiro, Sakai, Masato, Takahashi, Tomoko, Yamano, Takahiro, Yokoyama, Takuya, Ito, Hitomi, Katayama, Masayo, Kuroda, Emi, Ikeda, Toru, Kojo, Takuma, Yoshidome, Etsuo, Mizumachi, Rieko, Yamamoto, Akane, Yamasaki, Narihisa, Yamasaki, Yoshihiko, Wada, Jun, Eguchi, Jun, Higuchi, Chigusa, Katayama, Akihiro, Kinomura, Masaru, Kitagawa, Masashi, Kitamura, Shinji, Miyamoto, Satoshi, Morinaga, Hiroshi, Nakatsuka, Atsuko, Nojima, Ichiro, Shikata, Kenichi, Sugiyama, Hitoshi, Tanabe, Katsuyuki, Tsuji, Kenji, Uchida, Haruhito, Watanabe, Mayu, Hashimoto, Chie, Kato, Takahiro, Yamamoto, Sayaka, Wada, Takehiko, Fukagawa, Masafumi, Hamano, Naoto, Koizumi, Masahiro, Komaba, Hirotaka, Nakagawa, Yosuke, Iwamoto, Michiyo, Masutani, Kosuke, Katanosaka, Akane, Kiyota, Mayu, Uchi, Hikari, Ueda, Yuka, Yamamoto, Sonoka, Nagasu, Hajime, Itano, Seiji, Iwakura, Tsukasa, Kadoya, Hiroyuki, Kanda, Eiichiro, Kashihara, Naoki, Kidokoro, Kengo, Kondo, Megumi, Sasaki, Tamaki, Satoh, Minoru, Tokuyama, Atsuyuki, Umeno, Reina, Wada, Yoshihisa, Yamamoto, Toshiya, Yamanouchi, Yu, Abe, Masumi, Inukai, Yoko, Ogawa, Wataru, Asahara, Shunichiro, Fujii, Hideki, Goto, Shunsuke, Hirota, Yushi, Hosooka, Tetsuya, Kono, Keiji, Nishi, Shinichi, Okada, Yuko, Sakaguchi, Kazuhiko, Sugawara, Kenji, Takahashi, Michiko, Takai, Tomoko, Tamori, Yoshikazu, Watanabe, Kentaro, Kitajima, Miyu, Nishi, Misaki, Wada, Junko, Ito, Yasuhiko, Kamiya, Hideki, Asai, Akimasa, Asai, Nao, Asano, Saeko, Banno, Shogo, Ejima, Yohei, Hase, Hanako, Hayami, Tomohide, Himeno, Tatsuhito, Ishikawa, Takahiro, Ito, Mayumi, Iwagaitsu, Shiho, Kasagi, Rina, Kato, Yoshiro, Kato, Makoto, Kato, Koichi, Katsuno, Takayuki, Kawai, Miyuka, Kinashi, Hiroshi, Kondo, Masaki, Koshino, Masako, Matsuoka, Naoya, Morishita, Yoshiaki, Motegi, Mikio, Nakamura, Jiro, Shimoda, Hiromi, Sugiyama, Hirokazu, Tsunekawa, Shin, Yamaguchi, Makoto, Takahashi, Kazuyo, Watada, Hirotaka, Funayama, Takashi, Furukawa, Yasuhiko, Gohda, Tomohito, Goto, Hiromasa, Kaga, Hideyoshi, Kanaguchi, Yasuhiko, Kanazawa, Akio, Kaneko, Kayo, Kano, Toshiki, Kihara, Masao, Kimura, Shogo, Kobayashi, Takashi, Maiguma, Masayuki, Makita, Yuko, Mano, Satoshi, Mita, Tomoya, Miyatsuka, Takeshi, Murakoshi, Maki, Muto, Masahiro, Nakata, Masami, Nakata, Junichiro, Nishida, Yuya, Nohara, Nao, Ogihara, Takeshi, Sato, Daisuke, Sato, Junko, Sato, Hiroaki, Suzuki, Yusuke, Suzuki, Ruka, Suzuki, Hitoshi, Takagi, Miyuki, Tamura, Yoshifumi, Uchida, Toyoyoshi, Ueda, Seiji, Asawa, Miki, Miyaji, Minako, Nagashima, Eri, Shibata, Yoshie, Yanagisawa, Eri, Yamauchi, Toshimasa, Hirakawa, Yosuke, Nishi, Hiroshi, Shojima, Nobuhiro, Horikawa, Satoko, Nakayama, Yukiko, Yamada, Naoko, Omori, Yuki, Yano, Shintaro, Ioka, Miyabi, Kuwabara, Nahoko, Nagano, Remi, Nozawa, Megumi, Osawa, Yumi, Maegawa, Hiroshi, Kume, Shinji, Araki, Shinichi, Miyazawa, Itsuko, Morino, Katsutaro, Kawai, Ikuko, Sobata, Masumi, Takaoka, Motoko, Iwaita, Yasushi, Udagawa, Takashi, Inamori, Ami, Kawase, Aya, Yamanaka, Aya, Shimano, Hitoshi, Fujita, Akiko, Iwasaki, Hitoshi, Kai, Hirayasu, Osaki, Yoshinori, Saito, Chie, Sekiya, Motohiro, Tsunoda, Ryoya, Yamagata, Kunihiro, Nakamura, Rikako, Yamada, Aiko, Ohsugi, Mitsuru, Awazawa, Motoharu, Bouchi, Ryotaro, Hashimoto, Shota, Hashimoto, Makiko, Hisatake, Tomoko, Ihana, Noriko, Ishizuka, Koko, Izumi, Kazuo, Kajio, Hiroshi, Kobayashi, Michi, Kodani, Noriko, Maruyama, Koji, Matsumoto, Michihiro, Matsushita, Maya, Nakamura, Tomoka, Sugiyama, Takehiro, Tanabe, Akiyo, Terakawa, Aiko, Ueki, Kojiro, Orimo, Yuko, Ozawa, Takako, Takahira, Eriko, Yamasaki, Yoshimitsu, Haneda, Masakazu, Tomita, Tadahiro, Akimoto, Saori, Fujimoto, Akihiro, Ishihara, Kenji, Murakami, Chiho, Nishiyama, Akiyo, Toyonaga, Yukiko, Uozumi, Kana, Yamaji, Yukihiro, Shigehara, Tetsuya, Okajyo, Jun, Shimizu, Yukihiro, Iwasaki, Shingo, Fukao, Yuki, Furusho, Megumi, Nunokawa, Shintaro, Katagiri, Hideki, Izumi, Tomohito, Kaneko, Keizo, Kodama, Shinjiro, Miyazaki, Mariko, Munakata, Yuichiro, Nagasawa, Tasuku, Oe, Yuji, Sugawara, Hiroto, Takahashi, Kei, Hirata, Kazushige, Inomata, Keiko, Otomo, Shoko, Uchida, Taeko, Yamashita, Chigusa, Kiyosue, Arihiro, Tamura, Ryota, Dube, Francoi, Bolduc, Marilene, Talbot, Marie-Christine, Cham, Leslie, Lai, Vesta, Tse, Josephine, Jolly, Shivinder, Duck, Tabbatha, Lyle, Scott, Epp, Rachel, Galloway, Camille, Haskett, Susan, Matvienko, Elizabeta, Paulsen, Liam, Moist, Louise, Lozon, Zabrina, Ramsey, Tina, Whitmore, Brittany, Al-Zeer, Bader, Macleod, Paula, O'Sullivan, Aoife, Sheriff, Zainab, Tholl, Sam, Pandey, Amritanshu, Armstrong, Samantha, Gebeyehu, Bethelihem, Toth, Patrick, Goldenberg, Ronald, Jahangiriesmaili, Mahsa, Sanguila, Shariff, Suresh, Neethi, Talsania, Tanvi, Zalunardo, Nadia, Agharazii, Mohsen, Roussel, Marie-Pier, Saillant, Annie, Samson, France, Bajaj, Harpreet, Bhavsar, Miken, Dhall, Parul, Dhillon, Gagandeep, Grewal, Bhupinder, Nimbkar, Taniya, Madore, Francoi, Marcotte, Guylaine, Steen, Oren, Bullen, Mathura, Raguwaran, Shayani, Valleteau, Andre, Langlois, Marie-France, Brown, Christine, Steele, Andrew, Garrity, Melissa, Ghate, Taneera, Robinson, Holly, Tolibas, Michael, Tailor, Chetna, Elliott, Lauren, McClary-Wright, Christine, Boreky, Fadia, Fikry, Sameh, Ali, Ayesha, Barot, Chintankumar, Basily, Wagdy, Saram, Thisun, Varad, Vinay, Khandwala, Hasnain, Aguilera, Alex, Alvarez, Patricia, Gill, Balwinder, Huda, Nazihah, Navivala, Aamir, Pinto, Daniel, Bevilacqua, Micheli, Fung, Elaine, Hernandez, Geraldine, Mann, Puneet, Saini, Jaskiran, Rabasa-Lhoret, Remi, Bovan, Danijela, Devaux, Marie, Barnini, Cecilia, Leoncini, Giovanna, Manco, Luca, Nobili, Giulia, Piemontese, Matteo, Aucella, Filippo, Grifa, Rachele, Totaro, Francesco, La Manna, Gaetano, Capelli, Irene, Cianciolo, Giuseppe, Lerario, Sarah, Zappulo, Fulvia, Rosati, Alberto, Fani, Filippo, Spatoliatore, Giuseppe, Gesualdo, Loreto, Pesce, Francesco, Russo, Maria, Zippo, Maria, Cafiero, Cesira, Motta, Daria, Bianco, Simona, Bilucaglia, Donatella, Messa, Piergiorgio, Pavone, Laura, Tripodi, Federica, Vettoretti, Simone, Fioretto, Paola, Carraro, Gianni, Farnia, Filippo, Postal, Anna, D'Amelio, Alessandro, Cardone, Antonio, Piccinni, Giovanni, Aloisi, Annalisa, Scolari, Francesco, Alberici, Federico, Guerini, Alice, Saccà, Chiara, Salviani, Chiara, Zani, Roberta, DE NICOLA, Luca, Garofalo, Carlo, Elena Liberti, Maria, Minutolo, Roberto, Pennino, Luigi, Polese, Lucio, Mené, Paolo, Barberi, Simona, Falcone, Clorinda, Russo, Francesco, Caroppo, Maurizio, Santorelli, Gennaro, Rivera, Rodolfo, Santoro, Domenico, Giuffrida, Alfio, Zirino, Fortunata, Calvi, Cristina, Estienne, Luca, Gambaro, Giovanni, Gangemi, Concetta, Ortalda, Vittorio, Pessolano, Giuseppina, Grandaliano, Giuseppe, Baccaro, Rocco, Ferraro, Pietro, Mangiacapra, Roberto, Melandri, Marco, Foligno, Nadia, Quartagno, Rita, Vezzoli, Giuseppe, Brioni, Elena, and Group, EMPA-KIDNEY Collaborative

Subjects
chronic renal disease, empagliflozin, empa-kidney, General Medicine
Abstract

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; PConclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110. opens in new tab; EudraCT number, 2017-002971-24. opens in new tab.)

Published
2023

44. Gross hematuria after SARS-CoV-2 vaccination: questionnaire survey in Japan

Author

Ryousuke Aoki, Yoshihito Nihei, Naoki Kashihara, Hitoshi Suzuki, Masao Kihara, Yusuke Suzuki, Takashi Yokoo, Keiichi Matsuzaki, and Ichiei Narita

Subjects
Adult, Male, Nephrology, medicine.medical_specialty, COVID-19 Vaccines, Coronavirus disease 2019 (COVID-19), Physiology, Biopsy, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Kidney, urologic and male genital diseases, Gross hematuria, Young Adult, Japan, Surveys and Questionnaires, Physiology (medical), Internal medicine, Coronavirus 2019, medicine, Humans, Hematuria, Proteinuria, medicine.diagnostic_test, business.industry, Vaccination, mRNA vaccination, Correction, Glomerulonephritis, IgA nephropathy, Middle Aged, medicine.disease, female genital diseases and pregnancy complications, SARS-CoV-2 vaccination, Creatinine, Female, Original Article, Renal biopsy, medicine.symptom, business
Abstract

Background Recent clinical reports indicate a correlation between gross hematuria after the coronavirus 2019 (COVID-19) vaccination in patients with glomerulonephritis, especially immunoglobulin A nephropathy (IgAN). Furthermore, healthcare workers in Japan were initially vaccinated with an mRNA vaccine from February 17, 2021, and some of them experienced gross hematuria after receiving the vaccination. Methods We conducted a web-based survey of the councilor members of the Japanese Society of Nephrology (581 members, 382 facilities) to elucidate the relationship between gross hematuria and COVID-19 vaccination. Results In the first survey, 27 cases (female: 22, 81.5%) of gross hematuria were reported after receiving a COVID-19 vaccination. Of them, 19 (70.4%) patients were already diagnosed with IgAN at the occurrence of gross hematuria. Proteinuria appeared in eight of the 14 (57.1%) cases with no proteinuria before vaccination and hematuria in five of the seven (71.4%) cases with no hematuria before vaccination. The second survey revealed that a renal biopsy was performed after vaccination in four cases, all of whom were diagnosed with IgAN. Only one case showed a slightly increased serum creatinine level, and no patients progressed to severe renal dysfunction. Conclusion This study clarified the clinical features of gross hematuria after a COVID-19 vaccination. Because there was no obvious progression to severe renal dysfunction, safety of the COVID-19 vaccination is warranted at least in the protocol of inoculation twice.

Published
2021

45. Toward the development of a vibrant, super‐aged society: The future of medicine and society in <scp>J</scp> apan

Author

Katsuya Iijima, Tamao Endo, Wako Yumura, Masahiro Akishita, Yukiko K. Hayashi, Yasuyoshi Ouchi, Naoki Kashihara, Hidenori Arai, Kouetsu Ogasawara, and Masayuki Yokode

Subjects
Male, Geriatrics, Gerontology, medicine.medical_specialty, Population ageing, education.field_of_study, business.industry, Population, Nutrition Surveys, Social engagement, Quality of life (healthcare), Japan, Pharmaceutical Preparations, Health care, Quality of Life, Life expectancy, Humans, Medicine, Female, Disease management (health), Societies, business, education, Aged
Abstract

Background As Japan's population continues to age, it is estimated that the number of people aged ≥75 years will exceed 20 million by 2025. Furthermore, over the past 10 years, we have not reduced the difference between life expectancy and healthy life expectancy. Therefore, the extension of healthy life expectancy and the development of a healthy society are the most urgent issues. In terms of medical care, the changing times have inevitably led to changes in disease structures and medical demands; therefore, the medical delivery system has had to be changed to meet these demands. As dementia rapidly increases, it is important to address "frailty," a condition in which people become more vulnerable to environmental factors as they age, and there is a need to provide services to older people, particularly the old-old, that emphasize quality of life in addition to medical care. To realize a super-aged society that will remain vigorous and vibrant for many years, we need to rethink the future of Japanese medicine and healthcare, and the state of society. Current situation and problems Disparity between healthy life expectancy and average life expectancy in the realization of a healthy society It is a challenge to build a society with a long and healthy life expectancy through comprehensive prevention and management of lifestyle-related diseases, as well as the elucidation of the factors that explain sex differences in healthy life expectancy, based on the recognition that lifestyle-related diseases in midlife are risk factors for frailty and dementia in old age. Challenges in medical care for building a super-aged and healthy society The challenges include promoting clinical guidelines suitable for older people, including lifestyle-related disease management, promoting comprehensive research on aging (basic research, clinical research and community collaboration research), and embodying a paradigm shift from "cure-seeking medical care" to "cure- and support-seeking medical care." Furthermore, the key to the future of integrated community care is the development of a comprehensive medical care system for older people in each region and the development of the next generation of medical personnel. Dissemination of frailty prevention measures in a super-aged society The concept of frailty encompasses the meaning of multifacetedness and reversibility; therefore, a comprehensive approach is required, including the renewal of conventional prevention activities in each region, such as the nutritional status of older people, physical activity including exercise, and various opportunities for social participation and participation conditions. Challenges of an unstable diet and undernutrition in older people According to the National Health and Nutrition Examination Survey of Japan, energy and protein intakes are low in Japanese people aged ≥75 years; particularly in people aged ≥80 years, low and insufficient intake of nutrients are prominent. Undernutrition in older people is increasing and is more pronounced in women. There are multiple factors behind this, including social factors, such as living alone, eating alone, poverty and other social factors, as well as problems with access to food security. Pharmacotherapy for older people: measures against polypharmacy In addition to the problems of adverse drug events, drug interactions, duplication of effects and the presence of drugs that "require particularly careful administration," it is also necessary to take measures against polypharmacy in older people, as well as medical economic issues, such as high drug costs and large amounts of remaining drugs. Barriers to this measure include multiple medical institution visits for each disease, lack of coordination between professions, and lack of understanding by patients and families. Role of local communities in a healthy society The decline in the working-age population is also a major challenge; however, we need to make a shift to use this declining birthrate and aging population as an opportunity rather than a crisis. As we look ahead to the coming of the 100-year age of life, we rethink the creation of a comprehensive society and community, and aim to create an age-free society where everyone can play an active role and live in peace, regardless of age. Contents of the proposal In this report, we have put together a vision for the future of an aging Japanese society from a broader perspective of how the environment and local communities should be, rather than simply from the perspective of individual health. We aim to convey this proposal to the Ministry of Health, Labor and Welfare, the Ministry of Education, Culture, Sports, Science and Technology, the Cabinet Office, and various professional organizations. The paradigm shift from "cure-seeking medical care" to "cure- and support-seeking medical care" should be promoted for the development of a healthy society While further promoting pre-emptive medical care in the medical care for older people, the development of multidisciplinary medical guidelines appropriate for older people should be promoted at the same time. In addition, we should promote basic aging research, clinical research (including the long-term care field) and transitional research that cover regional areas. Furthermore, while promoting the paradigm shift from "cure-seeking medical care" to "cure- and support-seeking medical care," the development of various comprehensive medical treatment systems for older people and the strengthening of integrated community care systems should be promoted. Development of the next generation of medical personnel to comprehensively deal with geriatric care, including training geriatric specialists, should be promoted As the number of older people with multimorbidities and frailty rapidly increases in the future, we should promote the development of the next generation of medical personnel who can comprehensively handle medical care for older people, including training leading geriatricians in cooperation with multiple professions in the integrated community care system to provide sufficient medical care. Countermeasures for frailty in older people should be promoted from medical and community planning perspectives To address frailty, which requires comprehensive evaluation and intervention, the three pillars of frailty prevention (nutrition, exercise and social participation) should be incorporated and addressed as part of community development within each municipality, taking into account local characteristics. In particular, it is necessary to revise the way of thinking about nutrition management in older people and the guidelines of the societies in the field. In addition, it is important to strengthen industry-academia-government-private partnerships in each region, taking into account not only medical issues, but also social factors, and encourage the development of momentum in the entire region regarding measures against undernutrition in older people. Polypharmacy measures should be promoted in pharmacotherapy for older people It is necessary to promote cooperation between physicians and pharmacists, establish other multiprofessional cooperation systems, and develop medical and long-term care insurance systems to support this. It is also essential to change the public's mindset, and awareness-raising activities at all levels are required, including the enhancement of educational materials for medical caregivers and the general public. In addition, the economic impact of healthcare using big data should be timely clarified. Innovation in medical and urban planning perspectives should be promoted In the future, it will be necessary to modify and update multidisciplinary approaches such as social participation (e.g. participation in a salon) with a view to innovation in both medical care and community development, especially on the idea of a symbiotic community. In addition, industry-academia-government-private partnership is necessary, including all aforementioned, such as places where people can play an active role in the rest of their lives (such as employment), promotion of human connections, promotion of technology to support older people and support for daily life. Geriatr Gerontol Int 2021; 21: 601-613.

Published
2021

46. Efficacy and safety of esaxerenone (CS-3150) in Japanese patients with type 2 diabetes and macroalbuminuria: a multicenter, single-arm, open-label phase III study

Author

Sadayoshi Ito, Yasuyuki Okuda, Takashi Wada, Tomoko Sawanobori, Naoki Kashihara, Kenichi Shikata, and Masaomi Nangaku

Subjects
Male, Nephrology, medicine.medical_specialty, Hyperkalemia, Physiology, Urinary system, Urology, Renal function, Type 2 diabetes, Nephropathy, Macroalbuminuria, chemistry.chemical_compound, Phase III, Japan, Physiology (medical), Internal medicine, medicine, Albuminuria, Humans, Diabetic Nephropathies, Pyrroles, Sulfones, Urinary albumin-to-creatinine ratio, Aged, Mineralocorticoid Receptor Antagonists, Creatinine, business.industry, Incidence (epidemiology), Middle Aged, medicine.disease, Diabetes Mellitus, Type 2, chemistry, Esaxerenone, Original Article, Female, medicine.symptom, business, Glomerular Filtration Rate
Abstract

Background Esaxerenone has potential renoprotective effects and reduces the urinary albumin-to-creatinine ratio (UACR) in patients with diabetic kidney disease and overt nephropathy. We investigated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes (T2D) and macroalbuminuria (UACR ≥ 300 mg/g creatinine). Methods We conducted a multicenter, single-arm, open-label phase III study in 56 patients with T2D and UACR ≥ 300 mg/g creatinine with estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 and treated with a renin–angiotensin system inhibitor. Patients received esaxerenone for 28 weeks at 1.25 mg/day initially with titration to 2.5 mg/day based on serum potassium (K+) monitoring. Efficacy was evaluated as the change in UACR from baseline to week 28. Safety endpoints included adverse events (AEs), incidence of serum K+ increase, and change in eGFR from baseline. Results UACR decreased by 54.6% (95% CI 46.9%, 61.3%) on average from baseline (544.1 mg/g creatinine) to the end of treatment (246.8 mg/g creatinine); 51.8% of patients showed improvement to early nephropathy. AE incidence was 69.6%. Three patients (5.4%) had serum K+ levels ≥ 6.0 mEq/L or ≥ 5.5 mEq/L on two consecutive occasions. Hyperkalemia in two patients was transient and resolved during the treatment period. One patient discontinued following two consecutive serum K+ values ≥ 5.5 mEq/L. The maximum change from baseline in eGFR was − 8.3 mL/min/1.73 m2 at week 24. Conclusions Esaxerenone reduced UACR in Japanese patients with T2D and UACR ≥ 300 mg/g creatinine; more than half experienced a transition from UACR ≥ 300 mg/g creatinine to UACR Clinical trial registration JapicCTI-173696

Published
2021

47. Dual disruption of eNOS and ApoE gene accelerates kidney fibrosis and senescence after injury

Author

Arisa Ochi, Yasumasa Ikeda, Naoki Kashihara, Kojiro Nagai, Kensei Taguchi, Masanori Tamaki, Ken-ichi Aihara, Hideharu Abe, Masashi Miyoshi, Craig R. Brooks, Hiroyuki Kadoya, Kenji Nishimura, and Seiji Kishi

Subjects
Cyclin-Dependent Kinase Inhibitor p21, Male, 0301 basic medicine, Senescence, Apolipoprotein E, medicine.medical_specialty, Nitric Oxide Synthase Type III, Apolipoprotein B, Biophysics, Blood Pressure, Kidney, Biochemistry, Mice, 03 medical and health sciences, Apolipoproteins E, 0302 clinical medicine, Enos, Fibrosis, Internal medicine, Autophagy, medicine, Animals, Humans, Renal Insufficiency, Chronic, Endothelial dysfunction, Molecular Biology, Cellular Senescence, Mice, Knockout, biology, business.industry, Genes, p16, TOR Serine-Threonine Kinases, Cell Biology, Genes, p53, medicine.disease, biology.organism_classification, Lipids, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, biology.protein, business, Gene Deletion, DNA Damage, Kidney disease
Abstract

The relationship between cellular senescence and fibrosis in the kidney is being elucidated and we have identified it as therapeutic target in recent studies. Chronic kidney disease has also become a lifestyle disease, often developing on the background of hypertension and dyslipidemia. In this study, we clarify the effect of interaction between these two conditions on kidney fibrosis and senescence. Wild type mice (WT), apolipoprotein E-/- mice (ApoEKO), and endothelial nitric oxide synthase (eNOS)-/- ApoE-/- mice (DKO) were obtained by breeding. Unilateral ureteral obstruction (UUO) was performed on 8-10 week old male mice and the degree of renal tubular injury, fibrosis and kidney senescence were evaluated. DKO manifested elevated blood pressure, higher total cholesterol and lower HDL than WT. DKO showed sustained kidney injury molecule-1 protein expression. Kidney fibrosis was significantly higher in ApoEKO and DKO. mRNA expression of genes related to kidney fibrosis was the highest in DKO. The mRNA expression of Zinc-α2-Glycoprotein and heme oxygenase-1 were significantly decreased in DKO. Furthermore, mRNA expression of p53, p21 and p16 were increased both in ApoEKO and DKO, with DKO being the highest. Senescence associated β-gal positive tubule area was significantly increased in DKO. Increased DNA damage and target of rapamycin-autophagy spatial coupling compartments (TASCCs) formation was found in DKO. Mice with endothelial dysfunction and dyslipidemia developed kidney fibrosis and accelerated senescence even in young mice after injury. These data highlight the fact managing lifestyle-related diseases from a young age is important for CKD prevention.

Published
2021

48. Methods and rationale of the DISCOVER CKD global observational study

Author

Eric Wittbrodt, Glen James, Supriya Kumar, Alyshah Abdul Sultan, M. Arnold, Naoki Kashihara, Björn Holmqvist, David C. Wheeler, Jennie Medin, Katarina Hedman, Hiddo J.L. Heerspink, Mikhail Kosiborod, Carolyn S.P. Lam, Steven Fishbane, Mitja Lainscak, Peter Fenici, James A. Sloand, Carol A. Pollock, Hungta Tony Chen, Peter Stenvinkel, Juan Jesus Carrero, Eiichiro Kanda, Roberto Pecoits-Filho, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Kidney Center (GKC)

Subjects
medicine.medical_specialty, 030232 urology & nephrology, methods and rationale, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Epidemiology, Health care, medicine, AcademicSubjects/MED00340, Intensive care medicine, real-world evidence, Case report form, Transplantation, business.industry, Qualitative interviews, Original Articles, medicine.disease, quality of life, Nephrology, patient-reported outcomes, Biomarker (medicine), Observational study, business, chronic kidney disease, Kidney disease
Abstract

Background Real-world data for patients with chronic kidney disease (CKD), specifically pertaining to clinical management, metabolic control, treatment patterns, quality of life (QoL) and dietary patterns, are limited. Understanding these gaps using real-world, routine care data will improve our understanding of the challenges and consequences faced by patients with CKD, and will facilitate the long-term goal of improving their management and prognosis. Methods DISCOVER CKD follows an enriched hybrid study design, with both retrospective and prospective patient cohorts, integrating primary and secondary data from patients with CKD from China, Italy, Japan, Sweden, the UK and the USA. Data will be prospectively captured over a 3-year period from >1000 patients with CKD who will be followed up for at least 1 year via electronic case report form entry during routine clinical visits and also via a mobile/tablet-based application, enabling the capture of patient-reported outcomes (PROs). In-depth interviews will be conducted in a subset of ∼100 patients. Separately, secondary data will be retrospectively captured from >2 000 000 patients with CKD, extracted from existing datasets and registries. Results The DISCOVER CKD program captures and will report on patient demographics, biomarker and laboratory measurements, medical histories, clinical outcomes, healthcare resource utilization, medications, dietary patterns, physical activity and PROs (including QoL and qualitative interviews). Conclusions The DISCOVER CKD program will provide contemporary real-world insight to inform clinical practice and improve our understanding of the epidemiology and clinical and economic burden of CKD, as well as determinants of clinical outcomes and PROs from a range of geographical regions in a real-world CKD setting.

Published
2021

49. Nationwide survey of the coronavirus disease 2019 prevention and treatment systems for kidney disease patients: a study of Japanese Society of Nephrology-certified educational facilities

Author

Ken Sakai, Masaomi Nangaku, Toshio Shinoda, Hidetomo Nakamoto, Yuka Sugawara, Naoki Kashihara, Norio Hanafusa, Ryoichi Ando, Yoko Yoshida, Masao Iwagami, Kan Kikuchi, and Munekazu Ryuzaki

Subjects
Nephrology, medicine.medical_specialty, Time Factors, Coronavirus disease 2019 (COVID-19), Physiology, 030232 urology & nephrology, Certification, 030204 cardiovascular system & hematology, Nationwide survey, Hospitals, University, 03 medical and health sciences, Questionnaire survey, 0302 clinical medicine, Japan, Renal Dialysis, Risk Factors, Chronic kidney disease, Physiology (medical), Internal medicine, Pandemic, medicine, Humans, Infection control, Practice Patterns, Physicians', Renal Insufficiency, Chronic, Societies, Medical, Academic Medical Centers, Health Services Needs and Demand, Infection Control, Delivery of Health Care, Integrated, SARS-CoV-2, business.industry, COVID-19, Questionnaire, medicine.disease, Treatment Outcome, Health Care Surveys, Family medicine, Original Article, business, Kidney disease
Abstract

Background There are no reports of a large-scale survey on the infection prevention measures against coronavirus disease 2019 (COVID-19) in nephrology facilities. This study investigated the facility-level nephrology practices adopted during the COVID-19 pandemic and their associated challenges. Additionally, the treatment patterns and outcomes of chronic kidney disease (CKD) patients with COVID-19 were reviewed. Methods We conducted a nationwide questionnaire survey of 704 educational facilities that were certified by the Japanese Society of Nephrology (JSN) from October 20, 2020 to November 16, 2020. The questionnaire reviewed the facility characteristics, infection prevention measures taken during routine nephrology practice, impact of COVID-19 on nephrology practice, experiences in managing CKD patients with COVID-19, and nosocomial transmission in the nephrology unit. Results Of the 347 facilities that responded, 95.1% checked outpatients’ body temperatures and COVID-19 symptoms at their visits. To reduce face-to-face contact, 80% and 70% of the facilities lengthened the intervals between outpatient visits and introduced online/telephonic consultations, respectively. As a result, more than half of the hospitals experienced a decrease in the numbers of outpatients and inpatients (64% and 50%, respectively). During the study period, 347 facilities managed 479 CKD patients with COVID-19. Oxygen administration and mechanical ventilation were performed for 47.8% and 16.5% of the patients, respectively, with a 9.2% total mortality rate. Conclusion This survey demonstrated that JSN-certified educational nephrology facilities adopted multiple measures to manage the COVID-19 pandemic; however, they faced several challenges. Sharing these experiences could standardize these approaches and prepare us better for the future. Supplementary Information The online version contains supplementary material available at 10.1007/s10157-021-02082-z.

Published
2021

50. Infection prevention measures for patients undergoing hemodialysis during the COVID-19 pandemic in Japan: a nationwide questionnaire survey

Author

Hidetomo Nakamoto, Naoki Kashihara, Yoko Yoshida, Ryoichi Ando, Norio Hanafusa, Masaomi Nangaku, Toshio Shinoda, Masao Iwagami, Ken Sakai, Yuka Sugawara, Kan Kikuchi, and Munekazu Ryuzaki

Subjects
medicine.medical_specialty, Isolation (health care), Coronavirus disease 2019 (COVID-19), Urology, medicine.medical_treatment, Isolation, Nosocomial transmission, Japan, Internal medicine, Pandemic, medicine, Infection control, Position Statement, Personal protective equipment, Dialysis, PPEs, Transplantation, business.industry, SARS-CoV-2, Questionnaire, COVID-19, Diseases of the genitourinary system. Urology, Nephrology, Infection prevention measures, Hemodialysis, Emergency medicine, RC870-923, business, Disinfectants
Abstract

Background Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic affecting a variety of medical treatments, including hemodialysis. This study aims to investigate the implementation of infection control measures, to examine the shortage of personal protective equipment (PPE) and disinfectants, and to quantify the number of nosocomial COVID-19 transmissions in hemodialysis facilities in Japan during the pandemic. Methods We conducted a nationwide questionnaire survey between 20 October and 16 November 2020 (i.e., between the “second wave” and “third wave” in Japan) in the 4198 dialysis facilities of the Japanese Association of Dialysis Physicians and the Japanese Society for Dialysis Therapy. A total of 2227 facilities (53.0%) responded. The questionnaire consisted of (i) characteristics of facilities, (ii) infection prevention measures in routine dialysis practices, (iii) shortage of PPE, (iv) feasibility of various isolation measures, and (v) nosocomial transmission. Results Half of the responding facilities were hospitals with multiple departments, and the other half were clinics specialized in dialysis. Several infection prevention measures such as health checks of staff and patients, donning of masks before and after hemodialysis, and disinfection of frequently contacted areas were implemented during the COVID-19 pandemic. There was a significant improvement in the implementation rate of these measures during the pandemic, compared to before it, which reached over 90%. More than half of the facilities reported a shortage of disposable masks (67.2%) and hand sanitizer alcohol (56.7%). Isolation of COVID-19 patients in private rooms was possible only in 52.7% of the facilities. The majority of facilities (73.3%) could not accept COVID-19 dialysis patients due to lack of space and manpower. Nosocomial transmission of COVID-19 occurred in 4.0% of the facilities. Of those infected, 51.9% were staff. Conclusions This survey revealed that most hemodialysis facilities in Japan had improved implementation of infection control measures and had shortage of PPEs and disinfectants, though some facilities did not implement infection prevention measures adequately, mainly due to the limited space of the facility. It may be recommended that each facility immediately establishes isolation measures to prepare for the pandemic of COVID-19.

Published
2021

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