Maintained renin-angiotensin-aldosterone system inhibitor therapy with sodium zirconium cyclosilicate following a hyperkalaemia episode: a multicountry cohort study.

Background: This observational cohort study compared the likelihood of maintained (stabilized/up-titrated) renin-angiotensin-aldosterone system inhibitor (RAASi) therapy at 6 months following hyperkalaemia in patients with chronic kidney disease (CKD) and/or heart failure (HF) from the USA, Japan and Spain who received sodium zirconium cyclosilicate (SZC) for at least 120 days, relative to those with no prescription for a potassium (K+) binder. Methods: Using health registers and hospital medical records, patients with CKD and/or HF receiving RAASi therapy who experienced a hyperkalaemia episode were identified. Propensity score (PS) matching (1:4) was applied to balance the SZC cohort to the no K+ binder cohort on baseline characteristics. Logistic regression analysis was performed to compare the odds of maintained RAASi therapy at 6 months in the SZC versus no K+ binder cohorts. Results: The PS-matched SZC cohort included 565 (USA), 776 (Japan) and 56 (Spain) patients; the no K+ binder cohort included 2068, 2629 and 203 patients, respectively. At 6 months, 68.9% (USA), 79.9% (Japan) and 69.6% (Spain) in the SZC cohorts versus 53.1% (USA), 56.0% (Japan) and 48.3% (Spain) in the no K+ binder cohorts had maintained RAASi therapy. Meta-analysed across countries, the odds ratio of maintained RAASi therapy in the SZC cohort versus no K+ binder cohort was 2.56 (95% confidence interval 1.92-3.41; P < .0001). Conclusions: In routine clinical practice across three countries, patients treated with SZC were substantially more likely to maintain guideline-concordant RAASi therapy at 6 months following hyperkalaemia relative to patients with no K+ binder treatment.

Current dialyzer classification in Japan and mortality risk in patients undergoing hemodialysis.

Dialyzers are classified into five types based on their ß2-microglobulin clearance rate and albumin sieving coefficient: Ia, Ib, IIa, and IIb. In addition, a new classification system introduced a type S dialyzer. However, limited information is available regarding the impact of dialyzer type on patient outcomes. A cohort study was conducted using data from the Japanese Society for Dialysis Therapy Renal Data Registry database. Total 181,804 patients on hemodialysis (HD) were included in the study, categorized into four groups (type Ia, IIa, IIb, and S). The associations between each group and two-year all-cause mortality were assessed using Cox proportional hazard models. Furthermore, propensity score-matching analysis was performed. By the end of 2019, 34,185 patients on dialysis had died. After adjusting for all confounders, the risk for all-cause mortality was significantly lower in the type IIa, and S groups than in the type Ia group. These significant findings were consistent after propensity score matching. In conclusion, our findings suggest that super high-flux dialyzers, with a ß2-microglobulin clearance of ≥ 70 mL/min, may be beneficial for patients on HD, regardless of their albumin sieving coefficient. In addition, type S dialyzers may be beneficial for elderly and malnourished patients on dialysis.Trial registration number: UMIN000018641.

Evaluation of glomerular hemodynamic changes by sodium-glucose-transporter 2 inhibition in type 2 diabetic rats using in vivo imaging.

The mechanisms responsible for glomerular hemodynamic regulation with sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney disease due to type 2 diabetes remain unclear. Therefore, we investigated changes in glomerular hemodynamic function using an animal model of type 2 diabetes, treated with an SGLT2 inhibitor alone or in combination with a renin-angiotensin-aldosterone system inhibitor using male Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Afferent and efferent arteriolar diameter and single-nephron glomerular filtration rate (SNGFR) were evaluated in ZDF rats measured at 0, 30, 60, 90, or 120 minutes after the administration of a SGLT2 inhibitor (luseogliflozin). Additionally, we assessed these changes under the administration of the adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine), along with coadministration of luseogliflozin and an angiotensin II receptor blocker (ARB), telmisartan. ZDF rats had significantly increased SNGFR, and afferent and efferent arteriolar diameters compared to ZL rats, indicating glomerular hyperfiltration. Administration of luseogliflozin significantly reduced afferent vasodilatation and glomerular hyperfiltration, with no impact on efferent arteriolar diameter. Urinary adenosine levels were increased significantly in the SGLT2 inhibitor group compared to the vehicle group. A1aR antagonism blocked the effect of luseogliflozin on kidney function. Co-administration of the SGLT2 inhibitor and ARB decreased the abnormal expansion of glomerular afferent arterioles, whereas the efferent arteriolar diameter was not affected. Thus, regulation of afferent arteriolar vascular tone via the A1aR pathway is associated with glomerular hyperfiltration in type 2 diabetic kidney disease.

Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

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

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.

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

BACKGROUND: Information 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 METHODS: We 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. RESULTS: Using 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 (<20), yes = 2, no = 0; cancer, yes = 1, no = 0; dementia, yes = 3, no = 0; lower creatinine (<6.5 mg/dL), yes = 1, no = 0; lower albumin (<3.0 g/dL), yes = 3, no = 0; normal or high calcium (≥8.5 mg/dL), yes = 1, no = 0; and higher C reactive protein (>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) (p<0.001). CONCLUSION: We 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.

Mathematical expansion and clinical application of chronic kidney disease stage as vector field.

There are cases in which CKD progression is difficult to evaluate, because the changes in estimated glomerular filtration rate (eGFR) and proteinuria sometimes show opposite directions as CKD progresses. Indices and models that enable the easy and accurate risk prediction of end-stage-kidney disease (ESKD) are indispensable to CKD therapy. In this study, we investigated whether a CKD stage coordinate transformed into a vector field (CKD potential model) accurately predicts ESKD risk. Meta-analysis of large-scale cohort studies of CKD patients in PubMed was conducted to develop the model. The distance from CKD stage G2 A1 to a patient's data on eGFR and proteinuria was defined as r. We developed the CKD potential model on the basis of the data from the meta-analysis of three previous cohort studies: ESKD risk = exp(r). Then, the model was validated using data from a cohort study of CKD patients in Japan followed up for three years (n = 1,564). Moreover, the directional derivative of the model was developed as an index of CKD progression velocity. For ESKD prediction in three years, areas under the receiver operating characteristic curves (AUCs) were adjusted for baseline characteristics. Cox proportional hazards models with spline terms showed the exponential association between r and ESKD risk (p<0.0001). The CKD potential model more accurately predicted ESKD with an adjusted AUC of 0.81 (95% CI 0.76, 0.87) than eGFR (p<0.0001). Moreover, the directional derivative of the model showed a larger adjusted AUC for the prediction of ESKD than the percent eGFR change and eGFR slope (p<0.0001). Then, a chart of the transformed CKD stage was developed for implementation in clinical settings. This study indicated that the transformed CKD stage as a vector field enables the easy and accurate estimation of ESKD risk and CKD progression and suggested that vector analysis is a useful tool for clinical studies of CKD and its related diseases.

Associations of vitamin D receptor activators and calcimimetics with falls and effect modifications by physical activity: A prospective cohort study on the Japan Dialysis Outcomes and Practice Patterns Study.

INTRODUCTION: This study aimed to examine the associations of vitamin D receptor activators (VDRA) and calcimimetics use with falls. METHODS: This is a prospective cohort study on hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study. We excluded those who were unable to walk. The associations of VDRA or calcimimetics use with falls and effect modifications by physical activity were analyzed using marginal structural models. RESULTS: In total, 1875 patients were included. VDRA and calcimimetics use was not associated with falls (risk ratio [95% CI]: 1.13 [0.84-1.51] and 1.02 [0.72-1.44]). The risk ratio for falls associated with VDRA use was lower among those with poor physical activity (p for interaction <0.1). CONCLUSIONS: Although vitamin D receptor activators and calcimimetics use was not associated with falls, the lower risk ratio for falls with vitamin D receptor activators use among those with poor physical activity suggests that vitamin D receptor activators use might be beneficial among these patients.

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

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.

Hyperkalaemia-related reduction of RAASi treatment associates with more subsequent inpatient care.

BACKGROUND: Hyperkalaemia is a barrier to achieving optimal, guideline-directed treatment with renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with chronic kidney disease (CKD) and/or heart failure (HF). This study describes the association between hyperkalaemia-related RAASi treatment reduction and number of hospitalized days in patients with CKD and/or HF in Sweden and Japan. METHODS: Using data from health registers and hospital medical records, patients with CKD and/or HF currently receiving RAASi who experienced an index hyperkalaemia episode were identified and categorized as having maintained or reduced RAASi treatment post-index; propensity-score matching (1:1) was applied to balance the groups in terms of baseline characteristics. Changes in the number of all-cause, CKD-, and HF-related hospitalized days per patient-year during 6 months before versus after index, and the number of days alive and out of hospital (DAOH) during 6 months post-index were described. RESULTS: Overall, 20 824 and 7789 patients were included from Sweden and Japan, respectively, 42% and 38% of whom reduced their RAASi treatment after the index hyperkalaemia episode. During the 6 months post-index, all-cause hospitalization (95% confidence intervals) increased by 18.2 (17.0-19.2) days per person-year in Sweden and 17.9 (17.4-18.5) days per person-year in Japan among patients with reduced RAASi treatment compared with increases of 9.4 (8.6-10.4) and 8.5 (8.0-9.0) days per person-year, respectively, among patients with maintained RAASi treatment. Mean (standard deviation) DAOH were 121.5 (75.0) in Sweden and 141.7 (54.5) in Japan among patients with reduced RAASi treatment compared with 154.0 (51.3) and 157.5 (31.6) days, respectively, among patients with maintained RAASi treatment. CONCLUSION: Patients whose RAASi treatment was reduced after a hyperkalaemia episode had more hospitalized days and fewer DAOH compared with patients whose RAASi treatment was maintained.

Effect of overweight/obesity and metabolic syndrome on frailty in middle-aged and older Japanese adults.

Background: The potential for developing frailty exists in middle-aged and older adults. While obesity and metabolic syndrome (MetS) increase the risk of frailty in older adults, this relationship remains unclear in middle-aged adults, who are prone to developing lifestyle-related diseases. Objective: To examine the effect of overweight/obesity and MetS on frailty development in middle-aged and older Japanese adults using real-world data. Methods: This nationwide cohort study used exhaustive health insurance claims data of 3,958,708 Japanese people from 2015 to 2019 provided by the Japan Health Insurance Association. Participants aged ≥35 and < 70 years who received health checkups in 2015 were included. Multivariate logistic regression was used to assess the effect of body mass index (BMI) and MetS or MetS components (i.e., diabetes, hypertension, and dyslipidemia) in 2015 on frailty risk assessed using the hospital frailty risk score in 2019. Additionally, a subgroup analysis was performed to examine the interaction effects of MetS components and 4-year weight change (%) on frailty risk among participants who were overweight and obese (BMI ≥25 kg/m2). Results: In 2019, 7204 (0.2%) and 253,671 (6.4%) participants were at high and intermediate frailty risks, respectively. Obesity and MetS were independently associated with intermediate/high frailty risk (odds ratio (OR) 1.36, p < 0.05; OR 1.23, p < 0.05, respectively) and high frailty risk (OR 1.80, p < 0.05; OR 1.37, p < 0.05, respectively) in all participants. Although all MetS components were frailty risk factors, these effects diminished with age in both sexes. Subgroup analysis of patients with diabetes revealed that 5%-10% weight loss was associated with reduced frailty risk in both sexes. Conclusions: Obesity, MetS, and MetS components were independent frailty risk factors in middle-aged and older Japanese adults. Weight loss of up to 10% over 4 years prevented frailty in patients with diabetes who were overweight and obese.

eGFR slope as a surrogate endpoint for end-stage kidney disease in patients with diabetes and eGFR > 30 mL/min/1.73 m2 in the J-DREAMS cohort.

BACKGROUND: An analysis of European and American individuals revealed that a reduction in estimated glomerular filtration rate (eGFR) slope by 0.5 to 1.0 mL/min/1.73 m2 per year is a surrogate endpoint for end-stage kidney disease (ESKD) in patients with early chronic kidney disease. However, it remains unclear whether this can be extrapolated to Japanese patients. METHODS: Using data from the Japan diabetes comprehensive database project based on an advanced electronic medical record system (J-DREAMS) cohort of 51,483 Japanese patients with diabetes and a baseline eGFR ≥ 30 mL/min/1.73 m2, we examined whether the eGFR slope could be a surrogate indicator for ESKD. The eGFR slope was calculated at 1, 2, and 3 years, and the relationship between each eGFR slope and ESKD risk was estimated using a Cox proportional hazards model to obtain adjusted hazard ratios (aHRs). RESULTS: Slower eGFR decline by 0.75 mL/min/1.73 m2/year reduction in 1-, 2-, and 3-year slopes was associated with lower risk of ESKD (aHR 0.93 (95% confidence interval (CI) 0.92-0.95), 0.84 (95% CI 0.82-0.86), and 0.77 (95% CI 0.73-0.82), respectively); this relationship became more apparent as the slope calculation period increased. Similar results were obtained in subgroup analyses divided by baseline eGFR or baseline urine albumin-creatinine ratio (UACR), with a stronger correlation with ESKD in the baseline eGFR < 60 mL/min/1.73 m2 group and in the baseline UACR < 30 mg/gCre group. CONCLUSION: We found that changes in the eGFR slope were associated with ESKD risk in this population.

Glucose-lowering treatment pathways of individuals with chronic kidney disease and type 2 diabetes according to the Kidney Disease: Improving Global Outcomes 2012 risk classification.

AIMS: To describe treatment pathways for key glucose-lowering therapies in individuals with chronic kidney disease (CKD) and type 2 diabetes (T2D) using retrospective data from DISCOVER CKD (NCT04034992). METHODS: Data were extracted from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics data (2008-2020) and the US integrated Limited Claims and Electronic Health Records Database (LCED; 2012-2019). Eligible individuals were aged ≥18 years with CKD, identified by two consecutive estimated glomerular filtration rate (eGFR) measures (15-<75 mL/min/1.73 m2 ; 90-730 days apart; index date was the second measurement) and T2D. Chronological treatment pathways for glucose-lowering therapies prescribed on or after CKD index to end of follow-up were computed. Median time and proportion of overall follow-up time on treatment were described for each therapy by database and by eGFR and urinary albumin-to-creatinine ratio (UACR) categories. RESULTS: Of 36,951 and 4339 eligible individuals in the CPRD and LCED, respectively, median baseline eGFR was 67.8 and 64.9 mL/min/1.73 m2 ; 64.2 and 63.9% received metformin prior to index; and median (interquartile range) time on metformin during follow-up was 917 (390-1671) and 454 (192-850) days (accounting for ~75% of follow-up time in both databases). The frequency of combination treatment increased over time. There were trends towards decreased metformin prescriptions with decreasing eGFR and increasing UACR within each eGFR category. CONCLUSIONS: Individuals with CKD and T2D had many combinations of therapies and substantial follow-up time on therapy. These results highlight opportunities for improved CKD management.

Multimorbidity patterns in the working age population with the top 10% medical cost from exhaustive insurance claims data of Japan Health Insurance Association.

Although the economic burden of multimorbidity is a growing global challenge, the contribution of multimorbidity in patients with high medical expenses remains unclear. We aimed to clarify multimorbidity patterns that have a large impact on medical costs in the Japanese population. We conducted a cross-sectional study using health insurance claims data provided by the Japan Health Insurance Association. Latent class analysis (LCA) was used to identify multimorbidity patterns in 1,698,902 patients who had the top 10% of total medical costs in 2015. The present parameters of the LCA model included 68 disease labels that were frequent among this population. Moreover, subgroup analysis was performed using a generalized linear model (GLM) to assess the factors influencing annual medical cost and 5-year mortality. As a result of obtaining 30 latent classes, the kidney disease class required the most expensive cost per capita, while the highest portion (28.6%) of the total medical cost was spent on metabolic syndrome (MetS) classes, which were characterized by hypertension, dyslipidemia, and type 2 diabetes. GLM applied to patients with MetS classes showed that cardiovascular diseases or complex conditions, including malignancies, were powerful determinants of medical cost and mortality. MetS was classified into 7 classes based on real-world data and accounts for a large portion of the total medical costs. MetS classes with cardiovascular diseases or complex conditions, including malignancies, have a significant impact on medical costs and mortality.

eGFR slope as a surrogate endpoint for clinical study in early stage of chronic kidney disease: from The Japan Chronic Kidney Disease Database.

BACKGROUND: In clinical trials targeting early chronic kidney disease (CKD), eGFR slope has been proposed as a surrogate endpoint for predicting end-stage kidney disease (ESKD). However, it is unclear whether the eGFR slope serves as a surrogate endpoint for predicting long-term prognosis in Japanese early CKD populations. METHODS: The data source was the J-CKD-Database, which contains real-world data on patients with CKD in Japan. eGFR slope was calculated from the eGFR of each period, 1-year (1-year slope), 2-year (2-year slope), and 3-year (3-year slope), for participants with a baseline eGFR ≥ 30 ml/min/1.73 m2. The outcome was ESKD (defined as dialysis initiation or incidence of CKD stage G5). The relationship between eGFR slope and the sub-distribution hazard ratio (SHR) of ESKD with death as a competing event was investigated using a Fine-Gray proportional hazard regression model. RESULTS: The number of participants and mean observation periods were 7768/877 ± 491 days for 1-year slope, 6778/706 ± 346 days for 2-year slope, and 5219/495 ± 215 days for 3-year slope. As the eGFR slope decreased, a tendency toward a lower risk of ESKD was observed. Compared with the 1-year slope, there was a smaller variation in the slope values for the 2-year or 3-year slope and a greater decrease in the SHR; therefore, a calculation period of 2 or 3 years for the eGFR slope was considered appropriate. CONCLUSION: Even in Japanese patients with early stage CKD, a slower eGFR slope calculated from eGFR values over 2-3 years was associated with a decreased risk of ESKD.

Impact of chronic potassium binder treatment on the clinical outcomes in patients with hyperkalemia: Results of a nationwide hospital-based cohort study.

Introduction: Hyperkalemia (HK) is a common disorder in patients with heart failure or chronic kidney disease, and potassium binders (PBs) are recommended to control serum potassium (S-K) levels. Although HK is often a chronic condition, short-term and intermittent PBs treatment has been largely applied to control S-K levels, and little is known about the impact of long-term and chronic PBs treatment on clinical outcomes. Method: This retrospective cohort study was conducted using a Japanese claims database (April 2008-September 2018). HK was defined as at least two S-K ≥5.1 mmol/L within a 12-month(M) interval. The index date was defined as the initial PB prescription date, and the S-K values were examined at 3M, 6M, and 12M after the index. The medication possession ratio (MPR) was used to evaluate the length of the prescribed period of PB, as prescription refill was not allowed in Japan. Clinical outcomes were analyzed by comparing MPR <80% to MPR ≥80% using Cox proportional hazards regression. Results: We found 4,321 patients with HK and were on initial PB treatments, and 993 and 3,328 patients were categorized in the MPR <80% and MPR ≥80% groups, respectively. The mean prescription days ±SD in the MPR <80% and MPR ≥80% groups were 114.7 ± 9.1 and 1151.2 ± 22.5, respectively. S-K value with adjustment by covariates in MPR <80% and MPR ≥80% groups were 5.62 (95% CI: 5.57-5.68) and 5.72 (95% CI: 5.68-5.76) at index followed by 4.65 (95% CI: 4.58-4.71) and 4.57 (95% CI: 4.51-4.62) at 3M, respectively. The hazard ratios of incidence rates in hospitalization was 1.41 (p < 0.001), introduction of renal replacement therapy was 1.25 (p < 0.003), recurrent HK was 1.67 (p < 0.001), and decreased eGFR was 1.41 (p < 0.001), respectively. Conclusion: These results indicate a higher risk of adverse outcomes when PBs were not prescribed chronically, whereas S-K levels were similarly controlled. Chronic control with continued PBs rather than temporary treatment may be associated with the reduction of adverse clinical outcomes in patients with HK.

Association of Four Types of Vascular Access Including Arterial Superficialization with Mortality in Maintenance Hemodialysis Patients: A Nationwide Cohort Study in Japan.

INTRODUCTION: Vascular access usage varies widely across countries. Previous studies have evaluated the association of clinical outcomes with the three types of vascular access, namely, arteriovenous fistula (AVF), arteriovenous graft (AVG), and tunneled and cuffed central venous catheter (TC-CVC). However, little is known regarding the association between arterial superficialization (AS) and the mortality of patients. METHODS: A nationwide cohort study was conducted using data from the Japanese Society for Dialysis Therapy Renal Data Registry (2006-2007). We included patients aged ≥20 years undergoing hemodialysis with a dialysis vintage ≥6 months. The exposures of interest were the four types of vascular access: AVF, AVG, AS, and TC-CVC. Cox proportional hazard models were used to evaluate the associations of vascular access types with 1-year all-cause and cause-specific mortality. RESULTS: A total of 183,490 maintenance hemodialysis patients were included: 90.7% with AVF, 6.9% with AVG, 2.0% with AS, and 0.4% with TC-CVC. During the 1-year follow-up period, 13,798 patients died. Compared to patients with AVF, those with AVG, AS, and TC-CVC had a significantly higher risk of all-cause mortality after adjustment for confounding factors: adjusted hazard ratios (95% confidence intervals) - 1.30 (1.20-1.41), 1.56 (1.39-1.76), and 2.15 (1.77-2.61), respectively. Similar results were obtained for infection-related and cardiovascular mortality. CONCLUSION: This nationwide cohort study conducted in Japan suggested that AVF usage may have the lowest risk of all-cause mortality. The study also suggested that the usage of AS may be associated with better survival rates compared to those of TC-CVC in patients who are not suitable for AVF or AVG.

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

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<0.0001). Moreover, the risks of patients with high probabilities were higher than those with low probabilities: 22-variable model, hazard ratio of 104.9 (95% CI 70.81, 155.3); 8-variable model, 90.9 (95% CI 62.29, 132.7). Then, a Web-based risk-prediction system was actually developed for the implementation of the models in clinical practice. This study showed that a machine-learning-based Web system is a useful tool for the risk prediction and treatment of CKD patients.

Hypertensive Disorders of Pregnancy are Associated with Cardiovascular Disease in Middle- and Older-Aged Japanese Women.

AIM: Hypertensive disorders of pregnancy (HDP) are estimated to occur in up to 10% of all pregnancies and are associated with an increased risk of future cardiovascular disease (CVD) and chronic hypertension (HT). Therefore, we examined the impact of a history of HDP on CVD possibility in middle- and older-aged Japanese women. METHODS: We used the Tohoku Medical Megabank database to obtain the data of 26,024 menopausal women who were aged ≥ 50 years, had children, did not smoke, and did not have chronic kidney disease and to analyze the relationship between HDP history and CVD. RESULTS: A history of HDP was found in 4.6% of women. We divided the women into four groups according to the presence or absence of HDP and HT. The percentage of women with dyslipidemia, diabetes mellitus, and body mass index of ≥ 25 kg/m2 was the highest in the HDP＋ HT＋ group compared to the other groups (43.4%, 24.0%, and 45.2%, respectively). Adjusted odds ratio (OR) for the combined six CVD categories was higher for those with a history of HDP alone (OR [95% confidence interval [CI]]: 1.61 [1.03-2.53]). Moreover, the OR was significantly higher for those with combination with HDP history and HT (OR [95% CI]: 4.11 [3.16-5.35]). The prevalence of individual CVD was also the highest in the HT＋ HDP＋ group. CONCLUSION: An HDP history can influence the risk of CVD in Japanese women, indicating the importance of information about pregnancy outcomes in health management.

Immune checkpoint therapy and response biomarkers in non-small-cell lung cancer: Serum NY-ESO-1 and XAGE1 antibody as predictive and monitoring markers.

Immune checkpoint inhibitors (ICI) are key drugs in systemic therapy for advanced non-small-cell lung cancer (NSCLC) and have recently been incorporated into neoadjuvant and adjuvant settings for surgical resection. Currently, ICI combinations with cytotoxic agents are frequently used in clinical practice, although several ICI clinical trials have failed to produce long-term clinical benefits. Unfortunately, clinical benefit is moderate and limited considering physical and financial burden. Therefore, selecting appropriate patients and regimens for ICI therapy is important, and biomarkers are necessary for their selection. Tumor PD-L1 expression is universally used as a biomarker; however, PD-L1 assays show low analytical validity and reproducibility due to the visual-scoring system by pathologists. Recent tumor immunology studies explore that neoantigens derived from somatic mutations and the collaboration between T and B cells efficiently elicit antitumor responses. This suggests that high tumor mutational burden and T-cell infiltration are predictive biomarkers. However, B cells producing antibody (Ab) remain poorly understood and analyzed as biomarkers. We found that NY-ESO-1 and XAGE1 of cancer-testis antigen frequently elicit spontaneous humoral and cellular immune responses in NSCLC. Serum Ab against these antigens were detected in approximately 25% of NSCLC patients and predicted ICI monotherapy responses. In addition, the Ab levels were decreased with tumor shrinkage after ICI therapy. Thus, NY-ESO-1 and XAGE1 Ab are potentially biomarkers predicting and monitoring response to ICI therapy. For clinical applications, a fully-automated assay system measuring the Ab was developed. Here, we review current ICI therapy, tumor immunology, and biomarkers in NSCLC, and discuss the applicability of the serum biomarkers NY-ESO-1 and XAGE1 Ab.