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Aims: Japan started the Diabetic Nephropathy Aggravation Prevention Program. Its early impact was assessed in this study., Methods: This study used the Kokuho Database of patients with type 2 diabetes from program-implementing and non-implementing municipalities (fiscal years [FYs] 2015-2021). Implementing municipalities facilitated clinic visits and provided education to eligible patients. Average treatment effects on the treated in FYs 2016 and 2018 were evaluated using the inverse probability of treatment weighting. Comparison included intervened vs. non-intervened patients in program-implementing municipalities (Comparison A), intervened patients in program-implementing vs. eligible patients in non-implementing municipalities (Comparison B), and eligible patients in implementing and non-implementing municipalities (Comparison C)., Results: Overall, 89,611/89,685 patients from FY 2016/2018 were eligible. Among 68,125/68,170 patients in program-implementing municipalities, 1,470/1,819 were intervened. In Comparison A, the estimated effect of the program on ΔeGFR at 3 years were -0.4 (95 % confidence interval; -1.0, 0.2)/-0.4 (-0.9, 0.1) mL/min/1.73 m 2 in FY 2016/2018. Comparisons B and C demonstrated similar tendency; distribution of %change in eGFR varied between municipalities., Conclusions: Early in the program, renal function did not improve in the intervened patients or program-implementing municipalities. Diverse eGFR changes across municipalities highlighted diverse intervention outcomes, emphasizing the need of program refinement., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Takehiro Sugiyama reports financial support was provided by Government of Japan Ministry of Health, Labour and Welfare. Kazuyo Tsushita reports financial support was provided by Government of Japan Ministry of Health, Labour and Welfare. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To assess the cost-effectiveness of diabetic nephropathy treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors in Japanese clinical practice, considering diabetes-related complications., Materials and Methods: A population-based Monte Carlo simulation was used to estimate the cost-effectiveness for people with diabetic nephropathy who initiated pharmacotherapy with an SGLT2 inhibitor plus conventional treatment or conventional treatment alone, based on quality-adjusted life-years (QALYs) and healthcare costs. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation study (CREDENCE) and the Japanese Society for Dialysis Research statistical survey were the primary sources of probability and mortality, while Japanese Health Insurance Claims Data were the cost source. The state transition model included diabetic nephropathy, hospitalization due to cardiovascular disease, dialysis, and death. One-way and probabilistic sensitivity analyses were used to explore model uncertainty., Results: Using the threshold of JPY 5 000 000 per QALY, SGLT2 inhibitor plus conventional treatment was more cost-effective than conventional treatment alone, with an incremental cost-effectiveness ratio of JPY 654 309 per QALY. Treating 100 000 people, SGLT2 inhibitor plus conventional treatment prevented 2234 deaths and reduced 5793 fewer heart failure cases, 3967 fewer myocardial infarctions and stroke events. Sensitivity analysis affirmed the robustness of these results for patients aged under 70 years., Conclusions: The SGLT2 inhibitor treatment appeared to be cost-effective for the overall population of our study and particularly for younger patients (<70 years old). For older patients (≥70 years old), the cost-effectiveness was less clear and may require further evaluation. Decision-makers should consider this age-based heterogeneity when making recommendations about SGLT2 inhibitor treatment., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

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 (β = -0.609, p = .039; β = -2.298, p < .001; β = -0.936, p = .048; β = -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., (© 2024 John Wiley & Sons Ltd.)

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/1.73m 2 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 m 2 /year (95% CI -1.05 to -0.54) among SGLT2 inhibitors group and -1.78 mL/min/1.73 m 2 /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 m 2 /year (95% CI 0.5 to 1.38)), favoring SGLT2 inhibitors (p<0.001). Composite renal outcomes were observed 38 in the SGLT2 inhibitors group and 57 in the other glucose-lowering medications group (HR 0.64, 95% CI 0.42 to 0.97). There was no evidence of an interaction between SGLT2 inhibitors initiation and proteinuria., Conclusions: The benefits of SGLT2 inhibitors on renal outcomes are also applicable to older patients with DKD aged≥75 years., Competing Interests: Competing interests: YY received research support from AstraZeneca, Bayer, and Daiichi Sankyo and lecture fee from Otsuka Pharmaceutical and Torii Pharmaceutical. NK received lecture fee from AstraZeneca, Otsuka Pharmaceutical, Novartis, Daiichi Sankyo, Takeda Pharmaceutical, Kyowa Kirin, Mitsubishi Tanabe Pharma, Astellas Pharma, and scholarship donations from Astellas Pharma, Teijin Pharma, AstraZeneca, Kyowa Kirin, Bayer Yakuhin, Chugai Pharmaceutical, Otsuka Pharmaceutical, Nippon Boehringer Ingelheim, Daiichi Sankyo, Takeda Pharmaceutical Company Limited, additionally, funded by Daiichi Sankyo, AstraZeneca, Bayer, and Nobelpharma. KT received research support from AstraZeneca, Ono, Bayer, Kyowa Kirin, Otsuka Pharmaceutical, Takeda Pharmaceutical, and Daiichi Sankyo and received lecture fee from Novartis, AstraZeneca, Ono, Daiichi Sankyo, Takeda Pharmaceutical, Otsuka Pharmaceutical, Bayer, and Kyowa Kirin. NC and HA are employees of AstraZeneca., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This study aimed to evaluate the changes in glycemic control and diabetic complications over time in Japanese patients with juvenile-onset type 1 diabetes mellitus and to clarify the factors associated with the progression of diabetic complications., Methods: We tracked 129 patients with type 1 diabetes mellitus (21.8 ± 4.1 years old [mean ± SD] with a diabetes duration of 12.6 ± 5.7 years) for up to 19 years and analyzed data on glycated hemoglobin (HbA1c) and indicators related to the severity of diabetic complications (estimated glomerular filtration rate [eGFR], urinary albumin excretion rate [UAE], carotid intima-media thickness [CIMT], and brachial-ankle pulse wave velocity [baPWV]) using linear mixed model and decision tree analysis., Results: Although the HbA1c and UAE levels improved over time, the eGFR, CIMT, and baPWV worsened. Decision tree analysis showed that HbA1c and the glycoalbumin/HbA1c ratio for eGFR; HbA1c and systolic blood pressure for UAE; low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio, glycoalbumin/HbA1c ratio, and body mass index (BMI) for CIMT; and HbA1c for baPWV were associated factors., Conclusions: In this retrospective observational study, glycemic control and albuminuria improved; however, renal function and arteriosclerosis worsened over time. HbA1c levels, glycemic excursion, and blood pressure are associated with nephropathy progression. HbA1c levels, glycemic excursion, lipid levels, and BMI are associated with the progression of atherosclerosis., (© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Japan has the second highest prevalence of dialysis use in the world. Approximately 40% of patients who begin dialysis have diabetic kidney disease (DKD). Local governments and medical facilities are required to provide preventive measures against worsening diabetes mellitus (DM). However, the percentage of patients with DM who receive such screening or interventions for DKD is unclear. This study aimed to reveal to what extent screening for DKD and preventive measures against worsening DKD are performed in patients with DM, using an administrative database in a municipality., Methods: This was a cross-sectional study that used the Kyoto-city's administrative medical and long-term care database. Patients with a diagnosis of DM and receiving antidiabetic medication between 2013 and 2018 were defined as patients with DM and included. Patients with DKD were defined as those diagnosed with diabetic nephropathy or those with chronic kidney disease. We described the characteristics of patients with DM, diabetic complications, and extent of DKD screenings and preventive efforts against worsening of DM by fiscal year., Results: Across fiscal years, 25.8% to 27.5% of patient with DM had DKD. More than 3% of patients were on dialysis due DM in each fiscal year; approximately 15% started receiving dialysis that year. The percentage of patients who were regularly prescribed antidiabetic medication and received glycosylated hemoglobin testing ranged from 64.0% to 67.2% and from 30.6% to 36.5%, respectively. Urine microalbuminuria testing at least once a year occurred in 9.3% to 10.0%. The percentage of patients who received nutritional guidance ranged from 19.0% to 21.0%. Approximately 1% of patients received guidance for preventing DM from progressing to a disease that requires dialysis each fiscal year., Conclusion: This study from Japan, where a super-aging society has developed, using an administrative database in a municipality covering most of the elderly population clearly demonstrated an evidence-practice gap in efforts to prevent worsening of DKD. Strengthening cooperation between government and medical facilities and support for providing preventive measures against DKD are urgently needed., Competing Interests: Author MKU is employed by the company Healthtech Laboratory, Inc. TS and YuT are employed by the Kyoto University and HealthTech Laboratory Inc., Joint Research Fund. TI is an unpaid external director of HealthTech Laboratory Inc. and reported receiving joint research grants from Healthtech Laboratory Inc. and TIS Inc. YoT reported receiving grants from the Japan Society for the Promotion of Science during the study. TN reported receiving grants from I&H Co. Ltd. and Nakagawa Pharmacy Co. outside of the submitted work and fees from Otsuka Pharmaceutical Co., Pfizer Japan Inc., Merck & Co. KK, Chugai Pharmaceutical Co., Takeda Pharmaceutical Co., Janssen Pharmaceutical KK, Boehringer Ingelheim International GmbH, Eli Lilly Japan KK, Baxter Ltd., Mitsubishi Tanabe Pharma Co., Novartis Pharma KK, and Allergan Japan KK outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from a joint research grant from Healthtech Laboratory Inc. and Kyoto University, a joint research grant from Healthtech Laboratory Inc., Towa Pharmaceutical Co., Ltd., and TIS Inc., and a joint research grant from Kyoto University, Healthtech Laboratory Inc., and TIS Inc. The funders (Healthtech, Laboratory Inc., Towa Pharmaceutical Co., Ltd., and TIS Inc.) had the following involvement in the study: participation in the construction of the concept of the study, study design, analysis, and preparation of the manuscript., (Copyright © 2023 Tateyama, Shimamoto, Uematsu, Taniguchi, Nishioka, Yamamoto, Okada, Takahashi, Nakayama and Iwami.)

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., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

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., (© 2023. The Author(s).)

Background: The Kidney Disease: Improving Global Outcomes guidelines advocate the cause-glomerular filtration rate (GFR)-albuminuria (CGA) classification for predicting outcomes. However, there is a dearth of data supporting the use of the cause of chronic kidney disease. This study aimed to address how to incorporate a prior biopsy-proven diagnosis in outcome prediction., Methods: We examined the association of biopsy-proven kidney disease diagnoses with kidney failure with replacement therapy (KFRT) and all-cause death before KFRT in patients with various biopsy-proven diagnoses (n = 778, analysis A) and patients with diabetes mellitus labeled with biopsy-proven diabetic nephropathy (DN), other biopsy-proven diseases and no biopsy (n = 1117, analysis B)., Results: In analysis A, adding biopsy-proven diagnoses to the GFR-albuminuria (GA) classification improved the prediction of 8-year incidence of KFRT and all-cause death significantly regarding integrated discrimination improvement and net reclassification index. Fine-Gray (FG) models with KFRT as a competing event showed significantly higher subdistribution hazard ratios (SHRs) for all-cause death in nephrosclerosis {4.12 [95% confidence interval (CI) 1.11-15.2)], focal segmental glomerulosclerosis [3.77 (95% CI 1.09-13.1)]} and membranous nephropathy (MN) [2.91 (95% CI 1.02-8.30)] than in immunoglobulin A nephropathy (IgAN), while the Cox model failed to show significant associations. Crescentic glomerulonephritis had the highest risk of all-cause death [SHR 5.90 (95% CI 2.05-17.0)]. MN had a significantly lower risk of KFRT than IgAN [SHR 0.45 (95% CI 0.24-0.84)]. In analysis B, other biopsy-proven diseases had a lower risk of KFRT than biopsy-proven DN in the FG model, with death as a competing event [SHR 0.62 (95% CI 0.39-0.97)]., Conclusions: The CGA classification is of greater value in predicting outcomes than the GA classification., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Aim: Age-standardized incidence of end stage kidney disease requiring renal replacement therapy (RRT) has stabilized in men and declined in women in Japan since 1996. However, recent trends by primary kidney disease are unknown. The present study aimed to examine recent trends in incidence rates of RRT by primary kidney disease in Japan., Methods: Numbers of incident RRT patients aged ≥20 years by sex and primary kidney disease from 2006 to 2020 were extracted from the Japanese Society of Dialysis Therapy registry. Using the census population as the denominator, annual incidence rates of RRT were calculated and standardized to the WHO World Standard Population (2000-2025). Average annual percentage change (AAPC) and corresponding 95% confidence intervals (CIs) were calculated for trends using Joinpoint regression analysis., Results: From 2006 to 2020, the crude number of incident RRT patients due to nephrosclerosis increased by 132% for men and 62% for women. Age-standardized incidence rates of RRT due to nephrosclerosis increased significantly, by 3.3% (95% CI: 2.9-3.7) and 1.4% (95% CI: 0.8-1.9) per year for men and women, respectively. The AAPC of chronic glomerulonephritis (-4.4% [95% CI: -5.3 to -3.8] for men and -5.1% [95% CI: -5.5 to -4.6] for women) and diabetic nephropathy (-0.6% [95% CI: -0.9 to -0.3] for men and -2.8% [95% CI: -3.1 to -2.6] for women) significantly decreased from 2006 to 2020., Conclusion: Incident RRT due to chronic glomerulonephritis and diabetic nephropathy decreased, while the number and incident rates of RRT due to nephrosclerosis increased, from 2006 to 2020 in Japan., (© 2022 Asian Pacific Society of Nephrology.)

Objective: Previous reports have demonstrated the association of serum bilirubin levels with the progression of diabetic nephropathy. The objective of this study is to assess the association of basal bilirubin levels with progressive renal decline (PRD) and end-stage kidney disease (ESKD)., Methods: A total of 298 patients with diabetes who visited Kyushu University Hospital (Japan) were recruited and followed up for 10 years. PRD was defined as a negative change in estimated glomerular filtration ratio (eGFR) >3.7%/year, 2.5th percentile. Logistic regression analysis was performed to evaluate the association of total bilirubin levels with PRD and its cut-off point was determined by receiver operating characteristic (ROC) analysis. Kaplan-Meier method and Cox hazard regression analysis were used to evaluate the predictive ability of its cut-off point for ESKD., Results: Logistic regression model showed that total bilirubin levels were significantly associated with PRD, and ROC analysis showed that its cut-off point was 0.5 mg/dL. Kaplan-Meier method showed that the percent of patients who reached two endpoints, composite endpoint (ESKD or doubling of creatinine level) or 30% eGFR decline, was significantly higher in the low bilirubin group than in the high bilirubin group (18.5% vs 11.0%, P = 0.045; 49.1% vs 42.1%, P = 0.045, respectively, log-rank test). Cox hazard regression models confirmed the independence of the predictive ability of its cut-off point., Conclusions: Serum total bilirubin levels were negatively associated with PRD in diabetic nephropathy and its cut-off point was 0.5 mg/dL. It may be clinically useful for identifying patients at high risk of ESKD., Competing Interests: The authors have declared that no competing interests exist.

Background: It is important to identify additional prognostic factors for diabetic kidney disease. Materials & methods: Baseline levels of ten cytokines (APRIL/TNFSF13, BAFF/TNFSF13B, chitinase 3-like 1, LIGHT/TNFSF14, TWEAK/TNFSF12, gp130/sIL-6Rβ, sCD163, sIL-6Rα, sTNF-R1, sTNF-R2) were measured in two cohorts of diabetic patients. In one cohort (n = 777), 156 individuals were randomly sampled after stratification and their plasma samples were analyzed; in the other cohort (n = 69), serum samples were analyzed in all the individuals. The levels of cytokines between rapid (estimated glomerular filtration rate decline >5 ml/min/1.73 m 2 /year) and non-rapid decliners were compared. Results: Multivariate analysis demonstrated significantly high levels of LIGHT/TNFSF14, TWEAK/TNFSF12 and sTNF-R2 in rapid decliners. Conclusion: These three cytokines can be potential biomarkers for the progression of diabetic kidney disease.

Background: Existing reviews indicated that disease management for patients with diabetes may be effective in achieving better health outcomes with less resource utilization in the short term. However, the long-term results were inconsistent because of the heterogeneous nature of the study designs. In the present study, we evaluated the 5-year follow-up results of a local disease management program focused on diabetic nephropathy prevention under the universal public health insurance scheme in Japan., Methods: Patients diagnosed with type 2 diabetes who had stage 3 or 4 diabetic kidney disease and were aged between 20 and 75 years were invited to join a disease management program to support self-management and receive a recommended treatment protocol between 2011 and 2013. Follow-up data were collected from an electronic claims database for the public insurance scheme. Considering the non-random selection process, we prepared two control groups matched by estimated propensity scores to compare the incidence of diabetes-related complications, death, and resource utilization., Results: The treatment group was more likely to receive clinical management in accordance with the guideline-recommended medication. After propensity score matching, the treatment group had lower incidence of diabetic nephropathy and emergency care use than the control group selected from a beneficiary pool mainly under primary care. Comparisons between the treatment group and the control group with more selected clinical conditions did not show differences in the incidence rate and resource utilization., Conclusions: The present results demonstrated limited effectiveness of the program for reducing complication incidence and resource utilization during the 5-year follow-up. Further research on the long-term effectiveness of co-management by primary care physicians, subspecialists in endocrinology and nephrology, and nurse educators is required for effective management of diabetes-related nephropathy., (© 2022. The Author(s).)

Background: Disaster-related stress can increase blood pressure and the incidence of cardiovascular diseases. However, the role of massive disasters in the development of end-stage kidney disease (ESKD) remains unknown. We investigated the incidence and different causes of dialysis initiation in patients with chronic kidney disease in a city affected by the Great East Japan Earthquake., Methods: This was a single-center, retrospective observational study. All patients who initiated or were treated with dialysis at Kesennuma City Hospital between 2007 and 2020 were enrolled. The year of dialysis initiation was retrospectively determined based on the initiation date. The causative renal diseases that led to the need for dialysis initiation were divided into four groups: diabetic nephropathy, hypertensive renal disease, glomerulonephritis, and others., Results: Age at dialysis initiation differed significantly among the four groups (p = 0.0262). There was a significant difference in the numbers of the four groups before and after the Great East Japan Earthquake (p = 0.0193). The age of hypertensive renal disease patients was significantly higher than those of patients with diabetic nephropathy (p = 0.0070) and glomerulonephritis (p = 0.0386) after the disaster. The increasing number of dialysis initiations after the Great East Japan Earthquake appeared to be associated with changes in hypertensive renal diseases; the number peaked after 10 years., Conclusions: There was an increase in the number of dialysis initiations, especially caused by hypertensive renal diseases, for up to 10 years after the Great East Japan Earthquake., (© 2021. The Author(s).)

Aims: This study is aimed at clarifying the relationship between visit-to-visit variability of glycated hemoglobin (HbA1c) and the risk of diabetic kidney disease (DKD) and to identifying the most useful index of visit-to-visit variability of HbA1c., Methods: This clinic-based retrospective longitudinal study included 699 Japanese type 2 diabetes mellitus patients. Visit-to-visit variability of HbA1c was calculated as the internal standard deviation of HbA1c (HbA1c-SD), the coefficient of variation of HbA1c (HbA1c-CV), the HbA1c change score (HbA1c-HVS), and the area under the HbA1c curve (HbA1c-AUC) with 3-year serial HbA1c measurement data, and the associations between these indices and the development/progression of DKD were examined., Results: Cox proportional hazards models showed that the HbA1c-SD and HbA1c-AUC were associated with the incidence of microalbuminuria, independently of the HbA1c level. These results were verified and replicated in propensity score (PS) matching and bootstrap analyses. Moreover, the HbA1c-SD and HbA1c-AUC were also associated with oxidized human serum albumin (HSA), an oxidative stress marker., Conclusions: Visit-to-visit variability of HbA1c was an independent risk factor of microalbuminuria in association with oxidative stress among type 2 diabetes mellitus patients. HbA1c-AUC, a novel index of HbA1c variability, may be a potent prognostic indicator in predicting the risk of microalbuminuria., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2022 Yunyi Yan et al.)

Background: Epidemiological data regarding diabetic kidney disease are accumulated insufficiently in Japan. We prospectively investigated the incidence of end-stage renal disease (ESRD) and risk factors for progression of renal dysfunction in Japanese patients with type 2 diabetes., Methods: 4904 participants with type 2 diabetes (mean age 65 years, mean estimated glomerular filtration rate (eGFR) 75 mL/min/1.73 m 2 , proportion of eGFR  < 60 mL/min/1.73 m 2 21%) were investigated for the progression to ESRD requiring dialysis in multicenter outpatients registry for 5 years. Risk factors for progression of renal dysfunction (≥ 30% decline in eGFR from the baseline and annual eGFR decline rates) were evaluated., Results: The incidence rates of ESRD and all-cause mortality were 4.1/1000 person-years and 12.3/1000 person-years, respectively, and increased according to stages of chronic kidney disease (eGFR  < 30 mL/min/1.73 m 2 , incidence of ESRD 176.6/1000 person-years, all-cause mortality 57.4/1000 person-years). Incidence of  ≥ 30% decline in eGFR from the baseline was 16.4% at 5 years, and the mean annual decline rate was -1.84 mL/min/1.73 m 2 /year. The progression of renal dysfunction was significantly associated with older age, poor glycemic control, blood pressure, albuminuria, eGFR, previous cardiovascular disease, lifestyle factors (body mass index, reduced intake of dietary fiber, increased intake of sodium, no regular exercise), and depressive symptoms., Conclusions: This prospective study has emphasized the importance of multifactorial interventions on risk factors to suppress the high incidence of ESRD in Japanese patients with type 2 diabetes., (© 2021. Japanese Society of Nephrology.)

Background: Constipation was shown to be associated with higher risk of end-stage kidney disease or incident chronic kidney disease, although evidence in diabetic patients is lacking. The objective of the present study was to examine the association between constipation and diabetic kidney disease (DKD)., Methods: In total, 4826 Japanese outpatients with type 2 diabetes were classified according to presence or absence of constipation (defecation frequency < 3 times/week and/or taking laxative medication). DKD was defined as presence of decreased estimated glomerular filtration rate (eGFR < 60 ml/min/1.73 m 2 ), and/or albuminuria (urinary albumin-to-creatinine ratio ≥ 30 mg/g). Odds ratios for the presence of DKD were computed by a logistic regression model., Results: Compared with participants without constipation, the age- and sex-adjusted odds ratio for presence of DKD was 1.58 (95% confidence interval 1.38-1.82) for those with constipation. This association persisted following adjustment for potential confounding factors. Decreased defecation frequency and laxative use were also significantly associated with higher prevalence of DKD. Overall, these findings were identical even when decreased eGFR and albuminuria were separately analyzed., Conclusions: Constipation was associated with higher likelihood of DKD in patients with diabetes, suggesting the importance of clinical assessment of constipation to identify patients at high risk of progression of kidney disease., (© 2021. Japanese Society of Nephrology.)

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 m 2 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 m 2 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 < 300 mg/g creatinine., Clinical Trial Registration: JapicCTI-173696., (© 2021. The Author(s).)

Aims/introduction: As estimated glomerular filtration rate (eGFR) progression might correlate with cardiovascular prognosis, the correlation between 1-year decline in eGFR and cardiovascular incidences and renal outcome was investigated., Materials and Methods: The 1-year percentage decline in eGFR at the first observation year was calculated in a cohort of the standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) trial participants. The primary end-point was the composite cardiovascular end-point including the renal end-point. The associations between the incidence of each end-point and clinical markers were analyzed using the Cox proportional hazards regression model., Results: A total of 4,461 patients were analyzed. The mean observation period was 765.3 ± 363.1 days. The best cut-off value of 1-year eGFR decline was 0.099 in the first year for renal end-point prediction by receiver operating characteristic curve analysis. The area under the curve of the model including the 1-year eGFR decline of the first year was significantly larger than the model without it (0.943, 95% confidence interval 0.915-0.971 to 0.967, 95% confidence interval 0.950-0.983, P = 0.019). Primary end-point incidences and the renal end-point were much higher in rapid eGFR decliners compared with non-decliners (P < 0.0001). The cardiovascular end-point incidence, except for the renal end-point, was not different between the groups. According to Cox regression analysis, 1-year eGFR decline during the first year was a significant risk factor for the end-points, including the renal end-point, independent of albuminuria and eGFR at baseline., Conclusions: The 1-year eGFR decline rate provided useful information for cardiovascular end-point predictions, including the renal end-point, in addition to the conventional risk factors., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

We aimed to determine mortality risk in underweight patients with diabetic nephropathy for microalbuminuria or macroalbuminuria. We analyzed mortality and death-cause data from BioBank Japan, with baseline years 2003-2007. We analyzed mortality rates from all causes and ischemic heart disease, according to body mass index (<18.5, 18.5-21.9, 22-24.9 and ≥25 kg/m 2 ). The mean (standard deviation) of patient age, body mass index, and glycated hemoglobin at enrollment was 61.6 years (11.7 years), 25.0 kg/m 2 (4.4 kg/m 2 ) and 7.7% (1.5%), respectively. Hazard ratios of all-cause and ischemic heart disease mortality were highest (1.79 [P = 0.0001] and 2.95 [P = 0.027], respectively) in patients with body mass index <18.5 kg/m 2 , as compared with body mass index 22-24.9 kg/m 2 . All-cause mortality risk for body mass index <18.5 kg/m 2 was similar to that for current smokers (hazard ratio 1.70, P < 0.0001). Underweight could be a predictor of mortality risk in patients with diabetic nephropathy for microalbuminuria or macroalbuminuria., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

To evaluate the effect of multifactorial intervention on the onset and progression of diabetic kidney disease in the patients with type 2 diabetes, we analyzed the effects of intensified multifactorial intervention by step-wise intensification of medications and life-style modifications (intensive therapy treatment targets; HbA1c under 6.2%, blood pressure under 120/75 mmHg, low-density lipoprotein cholesterol under 80 mg/dL) comparing with the guideline-based standard care (conventional therapy treatment targets: HbA1c under 6.9%, blood pressure under 130/80 mmHg, low-density lipoprotein cholesterol under 120 mg/dL) on diabetic kidney disease. A total of 2540 eligible patients in the Japan Diabetes Optimal Integrated Treatment for three major risk factors of cardiovascular diseases (J-DOIT3) cohort were randomly assigned to intensive therapy (1269) and conventional therapy (1271) and treated for a median of 8.5 years. The prespecified kidney outcome measure was a composite of progression from normoalbuminuria to microalbuminuria or progression from normoalbuminuria to macroalbuminuria or progression from microalbuminuria to macroalbuminuria, serum creatinine levels elevated by two-fold or more compared to baseline, or kidney failure. Primary analysis was carried out on the intention-to-treat population. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. A total of 438 kidney events occurred (181 in the intensive therapy group and 257 in the conventional therapy group). Intensive therapy was associated with a significant 32% reduction in kidney events compared to conventional therapy and was associated with a change in HbA1c at one year from study initiation. Thus, prespecified analysis shows that intensified multifactorial intervention significantly reduced the onset and progression of diabetic kidney disease compared to currently recommended care., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Diabetic polyneuropathy (DPN) is the most common neuropathy manifested in diabetes. Symptoms include allodynia, pain, paralysis, and ulcer formation. There is currently no established radical treatment, although new mechanisms of DPN are being vigorously explored. A pathophysiological feature of DPN is abnormal glucose metabolism induced by chronic hyperglycemia in the peripheral nerves. Particularly, activation of collateral glucose-utilizing pathways such as the polyol pathway, protein kinase C, advanced glycation end-product formation, hexosamine biosynthetic pathway, pentose phosphate pathway, and anaerobic glycolytic pathway are reported to contribute to the onset and progression of DPN. Inhibitors of aldose reductase, a rate-limiting enzyme involved in the polyol pathway, are the only compounds clinically permitted for DPN treatment in Japan, although their efficacies are limited. This may indicate that multiple pathways can contribute to the pathophysiology of DPN. Comprehensive metabolic analysis may help to elucidate global changes in the collateral glucose-utilizing pathways during the development of DPN, and highlight therapeutic targets in these pathways.

Purpose: We aimed to investigate the characteristics of kidney disease in severely obese Japanese patients with type 2 diabetes mellitus (T2DM)., Methods: This was a cross-sectional study of severely obese patients (body mass index ≥35 kg/m 2 ) with T2DM treated at Jinnouchi Hospital, Kumamoto, Japan., Results: A total of 3128 T2DM patients visited the hospital during the survey period, of whom 55 patients (1.7%) were severely obese and 50 patients were enrolled. In terms of diabetic nephropathy (DN), twenty-five patients were stage 1 (non-DN, 50.0%), sixteen were stage 2 (32.0%), five were stage 3 (10.0%), and four were stage 4 (8.0%). There were significant differences in the presence of urinary occult blood (P = 0.01) and history of cardiovascular disease (CVD) (P = 0.04) between patients with DN (stages 2-4) and those without DN (stage 1). The presence of urinary occult blood (odds ratio [OR], 4.96; 95% confidence interval, 1.32-18.6; P = 0.02) was significantly associated with the presence of DN according to multivariate logistic regression analysis with forced inclusion of age, sex, and CVD history., Conclusions: Urinary occult blood may be a significant independent factor associated with the presence of nephropathy in severely obese Japanese patients with T2DM. The presence of urinary occult blood could thus be an important pathogenic factor in obesity-related nephropathy in patients with T2DM.

Bardoxolone methyl activates the Keap1/Nrf2 system that plays an important role in defense responses against oxidative stress. Importantly, bardoxolone methyl has demonstrated increases in estimated glomerular filtration rate (eGFR) in patients with diabetic kidney disease (DKD) in clinical studies. However, an overseas Phase 3 study of bardoxolone methyl in patients with stage G4 DKD was prematurely terminated due to an increased risk for heart failure, which was considered to have been caused by early-onset fluid overload. Subsequently, a Japanese Phase 2 study demonstrated, for the first time, that bardoxolone methyl directly improves GFR, which is a true indicator of kidney function, using the inulin clearance method. In Japan, bardoxolone methyl was designated for the treatment of DKD under the Priority Review and Designation (SAKIGAKE Designation) System established by the Ministry of Health, Labour and Welfare. A Japanese Phase 3 study, with endpoints such as a ≥ 30% decrease in eGFR, is currently ongoing to assess the efficacy and safety of bardoxolone methyl in more than 1,000 patients with stages G3 and G4 DKD who have no identified risk factors.

Backgrounds: Current guidelines recommend routine nephropathy monitoring, including microalbuminuria or proteinuria testing, for people with diabetes mellitus; however, its effect in terms of preserving renal function remains unclear. We conducted this study to examine the impact of routine nephropathy monitoring on subsequent changes in estimated glomerular filtration rate., Methods: We retrospectively identified non-elderly individuals with diabetes mellitus based on the prescription of hypoglycemic agents from a large Japanese database (JMDC, Tokyo, Japan) of screening for lifestyle diseases linked with administrative claims data. We collected data on baseline characteristics including age, sex, comorbidity, and laboratory data. We then examined the association between routine nephropathy monitoring results and change in estimated glomerular filtration rate using a propensity-score inverse probability of treatment weighting method., Results: Among 1,602 individuals who started taking hypoglycemic agents between 2005 and 2016, 102 (6.0%) underwent routine nephropathy monitoring during the first year of medication for diabetes mellitus. After adjusting for multiple confounding factors, there was no significant difference in subsequent estimated glomerular filtration rate changes between individuals with and without routine nephropathy monitoring (difference in percent change 0.11; 95% confidence interval -2.74 to 2.95)., Conclusion: Routine nephropathy monitoring was not associated with preserved renal function. Current recommendations for the universal application of nephropathy monitoring may have limited value to prevent renal dysfunction in non-elderly individuals with diabetes mellitus.

Background: Type 2 diabetes (T2D) is associated with renal impairment and vascular endothelial dysfunction. Therefore, this pathological connection is an important therapeutic target. Recent cardiovascular and renal outcome trials demonstrated that sodium glucose cotransporter 2 inhibitors (SGLT2is) consistently reduced the risks of cardiovascular and renal events and mortality in patients with T2D and various other background risks including chronic kidney disease (CKD). However, the precise mechanisms by which SGLT2is accords these therapeutic benefits remain uncertain. It is also unknown whether these SGLT2is-associated benefits are associated with the amelioration of endothelial dysfunction in patients with T2D and CKD., Methods: The PROCEED trial is an investigator-initiated, prospective, multicenter, open-label, randomized-controlled trial. The target sample size is 110 subjects. After they furnish informed consent and their endothelial dysfunction is confirmed from their decreased reactive hyperemia indices (RHI), eligible participants with T2D (HbA1c, 6.0-9.0%) and established CKD (30 mL/min/1.73 m 2  ≤ estimated glomerular filtration ratio [eGFR] < 60 and/or ≥ urine albumin-to-creatinine ratio 30 mg/g Cr) will be randomized (1:1) to receive either 50 mg ipragliflozin daily or continuation of background treatment (non-SGLT2i). The primary endpoint is the change in RHI from baseline after 24 weeks. To compare the treatment effects between groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for HbA1c (< 7.0% or ≥ 7.0%), age (< 70 y or ≥ 70 y), RHI (< 1.67 or ≥ 1.67), eGFR (< 45 mL/min/1.73 m 2 or ≥ 45 mL/min/1.73 m 2 ), and smoking status. Prespecified responder analyses will be also conducted to determine the proportions of patients with clinically meaningful changes in RHI at 24 weeks., Discussion: PROCEED is the first trial to examine the effects of ipragliflozin on endothelial dysfunction in patients with T2D and CKD. This ongoing trial will establish whether endothelial dysfunction is a therapeutic target of SGLT2is in this population. It will also provide deep insights into the potential mechanisms by which SGLT2is reduced the risks of cardiovascular and renal events in recent outcome trials. Trial registration Unique Trial Number, jRCTs071190054 (https://jrct.niph.go.jp/en-latest-detail/jRCTs071190054).

Introduction: The speed of declining kidney function differs among patients with diabetic nephropathy. This study was undertaken to clarify clinical and pathological features that affect the speed of declining kidney function in patients with diabetic nephropathy., Research Design and Methods: This study was design as multicenter retrospective study. The subjects (377 patients with diabetic nephropathy diagnosed by kidney biopsy at 13 centers in Japan) were classified into three groups based on the estimated glomerular filtration rate (eGFR) declining speed. The eGFR increasing group, the control group, and the eGFR declining group were divided at 0 and 5 mL/min/1.73 m 2 /year, respectively. Characteristics of clinicopathological findings of declining kidney function were evaluated., Results: The mean observation period of this study was 6.9 years. The control group, the eGFR increasing group, and the eGFR declining group included 81, 66, and 230 patients, respectively. The incidences of composite kidney events represented by 100 persons/year were 25.8 in the eGFR declining group and 2.0 in the eGFR increasing group. After adjustment for age, sex, systolic blood pressure, hemoglobin, and urinary albumin levels, three clinicopathological findings (urinary albumin levels, presence of nodular lesion, and mesangiolysis) were risk factors for inclusion in the eGFR declining group (the ORs were 1.49, 2.18, and 2.08, respectively). In contrast, the presence of subendothelial space widening and polar vasculosis were characteristic findings for inclusion in the eGFR increasing group (the ORs were 0.53 and 0.41, respectively)., Conclusions: As well as urinary albumin elevation, nodular lesion and mesangiolysis were characteristic pathological features of patients with fast declining kidney function., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing phenotype in patients with type 2 diabetes. However, it remains unclear whether its prognosis is poorer than that of other DKD phenotypes., Research Design and Methods: A total of 2,953 Japanese patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m 2 , enrolled in an observational cohort study in 2004, were followed until 2015. On the basis of albuminuria (>30 mg/g creatinine) and reduced eGFR (<60 mL/min/1.73 m 2 ) at baseline, participants were classified into the four DKD phenotypes-no-DKD, albuminuric DKD without reduced eGFR, nonalbuminuric DKD with reduced eGFR, and albuminuric DKD with reduced eGFR-to assess the risks of mortality, cardiovascular disease (CVD), and renal function decline., Results: During the mean follow-up of 9.7 years, 113 patients died and 263 developed CVD. In nonalbuminuric DKD, the risks of death or CVD were not higher than those in no-DKD (adjusted hazard ratio 1.02 [95% CI 0.66, 1.60]) and the annual decline in eGFR was slower than in other DKD phenotypes. The risks of death or CVD in nonalbuminuric DKD without prior CVD were similar to those in no-DKD without prior CVD, whereas the risks in nonalbuminuric DKD with prior CVD as well as other DKD phenotypes were higher., Conclusions: Nonalbuminuric DKD did not have a higher risk of mortality, CVD events, or renal function decline than the other DKD phenotypes. In nonalbuminuric DKD, the presence of macrovascular complications may be a main determinant of prognosis rather than the renal phenotype., (© 2020 by the American Diabetes Association.)

Objective: Dialysis patients have a higher incidence of stroke, and outcomes are often poor. Diabetic nephropathy (DN) is a stroke risk-factor, but the importance is unclear in dialysis patients. This study investigated the stroke features and risk factors in hemodialysis (HD) patients., Methods: All end-stage renal disease patients undergoing HD at Teraoka Memorial Hospital dialysis center were identified, with 195 recruited. Baseline clinical characteristics were collected, and the clinical outcomes and related factors of stroke in HD patients were retrospectively analyzed. The incidence rate of stroke and mortality were calculated using Kaplan-Meier survival analysis. Factors potentially related to stroke were analyzed by the log-rank test and Cox proportional hazards model for univariate and multivariate analysis., Results: In total, 21.0% (41 of 195) patients developed stroke. The incidence rates of stroke per 1000 patient-years were 53.6, 65.2, and 34.0 in all HD patients, DN patients, and non-DN patients, respectively. The cumulative incidence rates of stroke in all HD patients, DN patients, and non-DN patients per 5 years, and per 10 years were 22.6%, 43.5%; 28.8%, 59.6%; and 17.6%, 31.1%, respectively. The incidence rate of stroke in the DN patients was significantly higher than in the non-DN patients (P = .013). DN was the significant risk factor for stroke by multivariate analysis (hazard ratio 2.63, 95% confidence interval 1.08-7.85; P = .032)., Conclusions: This study revealed the trends of stroke in HD patients at a single institution in Japan. DN was shown to be a significant risk factor for stroke in HD patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The difficulty of adhering to a low-protein diet is a serious limitation of randomized controlled trials aimed at validating the efficacy of this therapy. In this observational study of patients with diabetic nephropathy, we examined the association of dietary protein intake (DPI) with renal outcome and mortality, taking into account the nutritional status., Methods: We conducted a single-center historical cohort study of 449 adult Japanese patients with type 2 diabetes and the urinary albumin-to-creatinine ratio of ≥ 300 mg/g or estimated glomerular filtration rate of < 30 mL/min/1.73 m 2 . DPI was estimated with a formula using nitrogen levels in spot urine and body mass index. Malnutrition was defined as the Geriatric Nutritional Risk Index of ≤ 98. The primary and secondary endpoints were renal replacement therapy (RRT) initiation and mortality before RRT initiation, respectively. The Fine and Gray subdistribution hazard model was used to determine the relative effects of DPI on the respective endpoint., Results: Decreased DPI was associated with lower incidence of RRT with an adjusted hazard ratio of 0.81 (95% confidence interval: 0.72-0.92, p < 0.001). The interaction between DPI and nutritional status with respect to mortality was significant (p interaction = 0.047). Decreased DPI was a risk factor for mortality in patients with malnutrition (p = 0.009) but not in those without malnutrition (p = 0.559)., Conclusions: In patients with type 2 diabetic nephropathy, lower DPI was associated with lower incidence of RRT initiation, suggesting beneficial effects of a low-protein diet on kidneys. Conversely, lower DPI might lead to increased mortality in patients with malnutrition.

Background: In Japan, there has been a remarkable increase in the incidence of type 2 diabetes in elderly patients. This study aimed to clarify the renal status in elderly patients with type 2 diabetes., Participants and Methods: There were 978 patients with type 2 diabetes who were classified into three groups: Group 1 (aged < 65 years of age), Group 2 (65-74 years of age), and Group 3 (≥ 75 years of age). Estimated glomerular filtration rate (eGFR) and urinary albumin level were measured. Moreover, the frequencies of each stage of chronic kidney disease for each group were determined, and differences among the three groups were analyzed., Results: The mean eGFR in Group 3 was 63.2 ± 19.1 mL/min/1.73 m 2 , which was lower than those in Group 1 (83.3 ± 22.8 mL/min/1.73 m 2 ) and Group 2 (72.0 ± 19.4 mL/min/1.73 m 2 ). The percentage of low eGFR (< 60 mL/min/1.73 m 2 ) with normo- and microalbuminuria in Group 3 was 31.9%, which was higher than the percentages observed in Group 1 (7.1%) or Group 2 (16.1%). Diabetic macroangiopathy was frequently observed in these patients. The frequency of low eGFR with proteinuria was 10.2%. In this group, diabetic micro- and macroangiopathies were frequently noted., Conclusion: In elderly patients with type 2 diabetes, renal dysfunction is characterized by low eGFR with normo- and microalbuminuria. In this group, macroangiopathy was more common than microangiopathy. The elderly patients with diabetes with low eGFR with proteinuria frequently had micro- and macroangiopathies.

Background: To determine the renal and cardiovascular prognosis and all-cause mortality of Japanese patients with type 2 diabetes showing a reduced estimated glomerular filtration rate (eGFR) without albuminuria., Methods: A population of 675 patients with type 2 diabetes was prospectively observed for 4 years to determine the renal and cardiovascular outcomes and mortality. The subjects were divided into the four groups: those with a preserved eGFR and no albuminuria (n = 306), a preserved eGFR and albuminuria (n = 151), a reduced eGFR and no albuminuria (n = 96), and a reduced eGFR and albuminuria (n = 122). The Cox proportional hazard model and Fine and Gray method were used to assess between-group differences in the risk of mortality and cardiovascular events., Results: In the group with a reduced eGFR, the eGFR value did not significantly change in the subjects without albuminuria (0 ± 8 mL/min/1.73 m 2 ), whereas it decreased continuously in those with albuminuria (-6 ± 12 mL/min/1.73 m 2 ). The incidence of cardiovascular events was significantly (P = 0.03) higher in the subjects with albuminuria (17%) than those without albuminuria (7%) in the group with a reduced eGFR. Cardiovascular events were significantly (P < 0.01) more frequent in the group with a reduced eGFR than in those with a preserved eGFR in both subjects with and without albuminuria., Conclusions: The risk of end-stage kidney disease in non-albuminuric subjects with a reduced eGFR is considered to be low. We should focus on cardiovascular prognosis, because these patients are still at high risk of cardiovascular events, even though the prognosis is better in comparison to albuminuric patients.

Oral health status is known to be associated with lifestyle-related diseases such as diabetes and chronic kidney disease. In Japan, around 40% of hemodialysis cases are patients with diabetic nephropathy. The aim of this study was to clarify the association between oral health status and diabetic nephropathy-related indices in Japanese middle-aged men. Sixty-six men (age range: 55-64 years) with ≥20 remaining teeth and who received public medical checkups and oral examinations were enrolled. We examined correlations of age, body mass index, HbA1c, HDL-C, LDL-C, neutral fat, serum creatinine, and the estimated glomerular filtration rate (eGFR) with the number of remaining teeth or the community periodontal index (CPI) score (periodontal pocket < 4 mm: 0, 4-6 mm: 1, ≥6 mm: 2). A positive correlation between the CPI score and serum creatinine and a negative correlation between CPI score and eGFR (Spearman's rank correlation coefficient, r = 0.459, p < 0.01, and r = -0.460, p < 0.01, respectively) were observed. The mean eGFR in the CPI score 0 group was significantly higher than that in the CPI score 1/2 group (82.6 vs. 70.7, Student's t -test, p < 0.01). Logistic regression analysis using eGFR as a dependent variable and age, CPI score, body mass index, HbA1c, and neutral fat as independent variables suggested that low eGFR (<60) could be attributed to CPI score (OR = 3.169, 95% CI: 1.031-9.742, p = 0.044). These results suggest a possible association between periodontal status and renal function in Japanese middle-aged men. Periodontal condition is controlled by oral prophylaxis, and periodontal disease and chronic kidney disease have some common risk factors. Thus, periodontal management can contribute to the prevention of severe chronic kidney disease., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2020 Masami Yoshioka et al.)

Background: The prognostic significance of glomerular extracapillary hypercellularity (EXHC) in diabetic kidney disease (DKD) is unclear. The aim of this study was to investigate the clinicopathological features and outcomes of DKD patients with EXHC., Methods: We studied 70 cases of renal biopsy-confirmed type 2 DKD that were diagnosed between 2004 and 2014 and compared the clinicopathological features and outcomes of 22 patients with EXHC (EXHC group) with those of 48 patients without EXHC (control group). All of the patients were Japanese. We assessed the renal biopsy specimens based on the Renal Pathology Society classification system. Clinical and laboratory data were collected at the time of the renal biopsy, and renal outcomes were assessed based on progression to end-stage renal disease (ESRD) requiring renal replacement therapy. The median duration of the observation period was 3 years., Results: In pathological features, nodular sclerosis (Kimmelstiel-Wilson lesions) was observed more frequently in the EXHC group than in the control group (63.6% vs. 35.4%, P = 0.027). There were no significant intergroup differences in clinical features or renal outcomes. Univariate and multivariate Cox regression analyses of all patients showed that a high level of proteinuria, a low initial eGFR, and severe interstitial inflammation were poor prognostic factors., Conclusions: EXHC is related to nodular sclerosis, which is a known risk factor for ESRD. Careful observation is needed during the follow-up of DKD patients with EXHC, although there were no significant differences in renal outcomes between the EXHC and control groups.

Background: To discriminatively evaluate the cost-saving effects of a disease management program for diabetic nephropathy patients through care process rectification and, subsequently, improved health outcomes., Methods: This study links public medical insurance claims data to the health records of a disease management program for diabetic nephropathy patients. To account for selection bias caused by the non-randomized allocation of the disease management program for diabetes patients, we adopted a fixed-effect model of panel data analysis. To discriminatively evaluate the cost-saving effects of the disease management program for diabetic nephropathy patients through care process rectification and, subsequently, improved health outcomes, we expanded the difference-in-differences analysis from the traditional two-period model to a three-period model, comprising the before-intervention, during-intervention, and after-intervention periods. Data were extracted from municipal public insurers in Kure, Japan., Results: The cost-reduction effect in terms of treatment costs from the before-intervention period to the during-intervention period (the rectification effect) was 4.02%, and the cost-saving effect from the during-intervention period to the after-intervention period (the health improvement effect) was 2.95%., Conclusions: A disease management program for diabetes patients organized by local public insurers in Japan reduced costs both by amending treatment processes and by subsequently improving the prognosis of the disease.

Background: Inadequate blood pressure control is one of the important causes of chronic kidney disease (CKD), but only a limited number of reports have examined blood pressure control in Japanese patients with pre-dialysis CKD. Differences in blood pressure control due to underlying renal disease in pre-dialysis patients with CKD were investigated in the present study using the baseline data of the Fukushima CKD cohort study., Methods: The study involved 1351 CKD patients, classified by underlying disease of primary renal disease, hypertensive nephropathy, diabetic nephropathy, other nephropathies, or unknown. Target blood pressure of CKD patients was defined as < 130/80 mmHg in patients under 75 years old with diabetes and/or proteinuria, and < 140/90 mmHg in other patients., Results: The achievement rate of target systolic blood pressure was lower in the diabetic and hypertensive nephropathy groups than in the primary renal disease group (33.3%, 46.0% vs. 68.1%, p < 0.001). However, the number of antihypertensive medications increased in the diabetic and hypertensive nephropathy groups compared to the primary renal disease group (2.16, 2.04 vs. 1.55, p < 0.001). Inadequate blood pressure control was independently related to the underlying renal disease, with a significant difference between diabetic nephropathy and primary renal disease (odds ratio 3.19; 95% confidence interval, 2.16-4.69; p < 0.001)., Conclusion: This study showed that blood pressure control differs by the underlying renal disease. Blood pressure control was poor especially in diabetic nephropathy despite multidrug combination antihypertensive treatment. It is necessary to verify whether strict blood pressure control improves patients' prognosis in diabetic nephropathy.

Objective: Glomerular 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 Methods: This 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) <60 mL/min/1.73 m². We classified patients into four groups based on the presence or absence of albuminuria and a decrease in eGFR to reveal the risk factors for DKD. We also performed a trajectory analysis and specified the prevalence and risk factors of early decliners with sequential eGFR data of 1955 patients in five facilities., Results: Of our cohort, 52% had DKD. Above all, 12% with a low eGFR but no albuminuria had no traditional risk factors, such as elevated glycated hemoglobin, elevated blood pressure, or diabetic retinopathy in contrast to patients with albuminuria but normal eGFR. Additionally, 14% of our patients were early decliners. Older age, higher basal eGFR, higher ACR, and higher systolic blood pressure were significantly associated with early decliners., Conclusions: The prevalence of DKD in this cohort was larger than ever reported. By testing eGFR yearly and identifying risk factors in the early phase of diabetes, we can identify patients at high risk of developing end-stage renal disease., Competing Interests: Competing interests: J-DREAMS is supported by Ministry of Health, Labour and Welfare, Japan Agency for Medical Research and Development, Japan Diabetes Society, Nippon Boehringer Ingelheim, Eli Lilly, Novo Nordisk Pharma, and Abbott Japan. KU reports lecture fees from Eli Lilly, Nippon Boehringer Ingelheim, Novo Nordisk, and Abbott Japan; grants and endowments from Eli Lilly, Nippon Boehringer Ingelheim, and Novo Nordisk., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The predictive value of diabetic retinopathy on end-stage kidney disease (ESKD) has not been fully addressed in patients with type 2 diabetes and diabetic kidney disease., Research Design and Methods: We studied 232 patients with type 2 diabetes and biopsy-proven diabetic kidney disease who were screened for diabetic retinopathy during the 1 month of kidney biopsy. We examined the association between retinopathy progression and renal lesions. We used Cox regression analyses to explore the risk of ESKD adjusting for known risk demographic and clinical variables. We assessed the incremental prognostic value of ESKD by adding diabetic retinopathy to the clinical variables., Results: The diabetic retinopathy progression positively correlated with all scores of renal lesions, especially with the glomerular-based classification (r=0.41), scores of interstitial fibrosis (r=0.41) and diffuse lesion (r=0.48). During a median follow-up of 5.7 years, 114 patients developed ESKD. Adjusting for known risk factors of ESKD, the HR for ESKD (patients with no apparent retinopathy as a reference) were 1.96 (95% CI 0.62 to 6.17) for patients with mild non-proliferative diabetic retinopathy (NPDR), 3.10 (95% CI 1.45 to 6.65) for patients with moderate NPDR, 3.03 (95% CI 1.44 to 6.37) for patients with severe NPDR, and 3.43 (95% CI 1.68 to 7.03) for patients with proliferative diabetic retinopathy, respectively. Addition of the retinopathy grading to the clinical model alone improved the prognostic value (the global χ 2 statistic increased from 155.2 to 164.5; p<0.001), which is an improvement equivalent to the addition of the renal lesion grading to the clinical model., Conclusions: Retinopathy progression appeared to be associated with renal lesions and the development of ESKD. Our findings suggest that diabetic retinopathy and kidney disease share the same magnitude of disease progression, and therefore diabetic retinopathy may be useful for prognosticating the clinical course for diabetic kidney disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Imarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria., Design, Setting, Participants, & Measurements: This was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing., Results: Changes in the urine albumin-to-creatinine ratio from baseline to the end of treatment were 16% (placebo), -16% (imarikiren 5 mg), -27% (imarikiren 20 mg), -38% (imarikiren 40 mg), -39% (imarikiren 80 mg), and -31% (candesartan cilexetil 8 mg). Urine albumin-to-creatinine ratio reductions from baseline were statistically significant in all imarikiren groups versus placebo ( P <0.001 each) as well as for candesartan cilexetil 8 mg versus placebo ( P <0.001). Remission rates (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased ≥30% from baseline) were higher in all imarikiren groups versus the placebo group. Incidence of adverse events was higher in the imarikiren 80-mg group (52%) versus placebo (42%) and candesartan cilexetil (43%) groups. Incidence of adverse events for the other imarikiren groups ranged from 33% to 42%. Adverse events were mild or moderate in severity. All imarikiren doses were well tolerated., Conclusions: Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria., (Copyright © 2019 by the American Society of Nephrology.)

Aim: The renoprotective effect of sodium-glucose cotransporter 2 inhibitors is thought to be due, at least in part, to a decrease in blood pressure. The aim of this study was to determine the renal effects of these inhibitors in low blood pressure patients and the dependence of such effect on blood pressure management status., Methods: The subjects of this retrospective study were 740 patients with type 2 diabetes mellitus and chronic kidney disease who had been managed at the clinical facilities of the Kanagawa Physicians Association. Data on blood pressure management status and urinary albumin-creatinine ratio were analyzed before and after treatment., Results: Changes in the logarithmic value of urinary albumin-creatinine ratio in 327 patients with blood pressure < 130/80 mmHg at the initiation of treatment and in 413 patients with BP above 130/80 mmHg were -0.13 ± 1.05 and -0.24 ± 0.97, respectively. However, there was no significant difference between the two groups by analysis of covariance models after adjustment of the logarithmic value of urinary albumin-creatinine ratio at initiation of treatment. Changes in the logarithmic value of urinary albumin-creatinine ratio in patients with mean blood pressure of <102 mmHg ( n = 537) and those with ≥102 mmHg ( n = 203) at the time of the survey were -0.25 ± 1.02 and -0.03 ± 0.97, respectively, and the difference was significant in analysis of covariance models even after adjustment for the logarithmic value of urinary albumin-creatinine ratio at initiation of treatment ( p < 0.001)., Conclusion: Our results confirmed that blood pressure management status after treatment with SGLT2 inhibitors influences the extent of change in urinary albumin-creatinine ratio. Stricter blood pressure management is needed to allow the renoprotective effects of sodium-glucose cotransporter 2 inhibitors., Competing Interests: The author and coauthors declare no conflict of interest associated with this study., (Copyright © 2019 Kazuo Kobayashi et al.)

Background: Glucagon stimulation test (GST) is often employed to assess the insulin reserve of the pancreatic beta cells in diabetic subjects. The clinical significance of the increment of plasma glucose (Δglucose) by exogenous glucagon during GST has not been elucidated. We investigated the relationship between Δglucose and clinical parameters including the liver and renal function in type 2 diabetic subjects, since we hypothesized that Δglucose is associated with the liver and renal function reflecting the capacity for gluconeogenesis in the organs., Methods: A total of 209 subjects with type 2 diabetes who underwent GST during admission were included in this cross-sectional study. We defined the difference between plasma glucose at fasting and 6 min after intravenous injection of 1 mg glucagon as Δglucose. We assessed correlations between Δglucose and clinical parameters such as diabetic duration, BMI, HbA1c, beta cell function, serum free fatty acids (FFA) which is known to stimulate gluconeogenesis, liver function, the indices of liver function, renal function, and urinary albumin excretion (UAE)., Results: In correlation analysis, Δglucose positively correlated to FFA and estimated glomerular filtration rate (eGFR), but inversely to serum creatinine and cystatin C, although Δglucose showed no correlation with both liver function and the indices of residual liver function. Multiple regression analysis revealed that Δglucose was an independent determinant for the eGFR after 1 year, equally BMI, HbA1c, serum lipids, and UAE, which are known as the predictors for the development of chronic kidney disease., Conclusion: Our results suggest that Δglucose during GST might be related to gluconeogenesis in the kidney and could be the determinant of future renal function in type 2 diabetes.

Aims/introduction: To examine the three-dimensional morphology and vascular endothelial growth factor (VEGF) expression of skin microvasculature in patients with type 2 diabetes in relation to neuropathy, retinopathy and nephropathy., Materials and Methods: The present study enrolled 17 individuals with type 2 diabetes and 16 without. Skin sections were double-immunostained for type IV collagen and VEGF-A or protein gene product 9.5. Projected images from confocal microscopy served to quantify the occupancy rate of subepidermal type IV collagen-immunoreactive microvascular basement membrane area (OR-T4MBM), subepidermal VEGF-A-immunoreactive area and the VEGF/T4MBM ratio, as well as the protein gene product 9.5-immunoreactive intraepidermal nerve fiber density. Reduced intraepidermal nerve fiber density was applied for the diagnosis of neuropathy, fundic ophthalmoscopy and fluorescein angiography for retinopathy, and microalbuminuria or persistent proteinuria for nephropathy., Results: A total of 12 patients with diabetes had neuropathy, 10 had retinopathy and eight had nephropathy. Regardless of the presence or absence of neuropathy, retinopathy or nephropathy, OR-T4MBM was significantly increased in patients with diabetes compared with individuals without diabetes. In contrast, VEGF/T4MBM ratio was significantly decreased in those with neuropathy and retinopathy, as well as in those with and without nephropathy, whereas a trend toward a decreased VEGF/T4MBM ratio was seen in patients without retinopathy, as compared with individuals without diabetes., Conclusions: The present study is the first report to show that cutaneous microangiopathy, as indicated by subepidermal microvascular proliferation and impaired VEGF expression, appears to occur before the development of overt clinical neuropathy, retinopathy or nephropathy in patients with type 2 diabetes., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aim: This study examined the association among the onset of diabetic kidney disease (DKD), blood glucose levels (HbA1 C ), and body mass index (BMI) in Japanese patients with type 2 diabetes mellitus., Methods: Patients eligible for this study included those with type 2 diabetes who visited the outpatient clinic at Kawasaki Medical School Hospital between 2000 and 2018 and were followed up for more than two years. The Cox proportional hazards model was used in four categories of subjects: at the beginning of the follow-up period, "controlled" or "uncontrolled" glycemic control based on HbA1c and "overweight" or "non-overweight" based on BMI., Results: After dividing the participants into four categories according to HbA1c (lower than 7.0% (C) or higher (U)), and BMI (25 kg/m 2 or higher (O) or lower (N)), hazard ratios for groups CO, UN, and UO were 1.40 (95% CI 1.03-1.90, P = 0.030), 1.40 (1.04-1.88, P = 0.027), and 1.54 (1.12-2.11, P = 0.008), respectively, compared with the CN reference group, after adjustment was made for age, sex, duration of diabetes, and medication for hypertension or dyslipidemia., Conclusion: Maintenance of both an HbA1c level lower than 7.0% and a BMI lower than 25 kg/m 2 was important for the prevention of DKD in Japanese patients with type 2 diabetes mellitus. Both factors had a similar effect on DKD in this study., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Advanced glycation end products and their precursors cause vascular damage through oxidative stress. We investigated the hypothesis that methylglyoxal (MG), 3-deoxyglucosone (3-DG) and pentosidine influence outcomes of chronic kidney disease (CKD) patients., Methods: We conducted a 3 years prospective observational study involving 150 outpatients at CKD stages 3-5. At enrolment, MG, 3-DG and pentosidine plasma concentrations were measured; patients were divided into tertiles according to the concentration of each substance. The primary endpoint was death, a cardiovascular event or end-stage renal disease. Survival analysis was performed using the Cox regression model., Results: The patients' mean age was 62 ± 12 years, 97 were men, and 20 had diabetic nephropathy. The mean estimated glomerular filtration rate was 25.0 ± 12.1 mL/min per 1.73 m 2 , which negatively correlated with MG but not with 3-DG and pentosidine. Forty-eight patients reached the primary endpoint. Compared with the lowest MG tertile, the hazard ratio for the primary endpoint was 7.57 (95% confidence interval (CI): 1.71-33.54) in the middle tertile and 27.00 (CI: 6.46-112.82) in the highest tertile. When adjusted for characteristics at baseline, the corresponding hazard ratio decreased to 2.09 (CI: 0.37-11.96) and 6.13 (CI: 0.97-38.82), but MG tertile remained an independent risk factor for the primary endpoint. However, 3-DG and pentosidine were not related to the primary outcome., Conclusion: Methylglyoxal has a close clinical association with CKD. Higher MG concentrations may contribute renal function deterioration in CKD. In CKD patients, MG concentration might be useful when determining the prognosis., (© 2018 Asian Pacific Society of Nephrology.)

Background: The Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria., Methods: We conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0-10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m 2 , and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24., Results: Baseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P < 0.001). In addition, changes in morning, evening, and nocturnal home BP from baseline were as follows: morning systolic/diastolic BP - 8.32 ± 11.42/- 4.18 ± 5.91 mmHg (both P < 0.001), evening systolic/diastolic BP - 9.57 ± 12.08/- 4.48 ± 6.45 mmHg (both P < 0.001), and nocturnal systolic/diastolic BP - 2.38 ± 7.82/- 1.17 ± 5.39 mmHg (P = 0.0079 for systolic BP, P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR., Conclusions: In Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction. Trial registration The study is registered at the UMIN Clinical Trials Registry (UMIN000018930; http://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from July 1, 2015 to August 1, 2018.

Aims/introduction: Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes., Materials and Methods: Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross-sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed., Results: The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30-60 mL/min/1.73 m 2 ) and severely reduced eGFR (<30 mL/min/1.73 m 2 ) increased. Severely reduced eGFR was observed mainly in the patients with macroalbuminuria, regardless of year. Conversely, the prevalence of moderately reduced eGFR increased in the patients without macroalbuminuria. Both macroalbuminuria and moderately reduced eGFR without macroalbuminuria in the 2014 cohort were refractory to the recently recommended intensive therapy. Finally, we showed that obesity accompanied by vascular dysfunction was a risk factor for the development of albuminuria, and that age-dependent arterial stiffness was associated with reduced eGFR without macroalbuminuria in the 2014 cohort., Conclusions: During the past 20 years in Japan, the prevalence of albuminuria declined, whereas that of reduced eGFR increased. Additionally, obesity- and high age-related vascular damage seems to be associated with macroalbuminuria and reduced eGFR without macroalbuminuria, respectively., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objective: Clinicopathological characteristics, renal prognosis, and mortality in patients with type 2 diabetes and reduced renal function without overt proteinuria are scarce., Research Design and Methods: We retrospectively assessed 526 patients with type 2 diabetes and reduced renal function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m 2 ), who underwent clinical renal biopsy and had follow-up data, from Japan's nationwide multicenter renal biopsy registry. For comparative analyses, we derived one-to-two cohorts of those without proteinuria versus those with proteinuria using propensity score-matching methods addressing the imbalances of age, sex, diabetes duration, and baseline eGFR. The primary end point was progression of chronic kidney disease (CKD) defined as new-onset end-stage renal disease, decrease of eGFR by ≥50%, or doubling of serum creatinine. The secondary end point was all-cause mortality., Results: Eighty-two patients with nonproteinuria (urine albumin-to-creatinine ratio [UACR] <300 mg/g) had lower systolic blood pressure and less severe pathological lesions compared with 164 propensity score-matched patients with proteinuria (UACR ≥300 mg/g). After a median follow-up of 1.9 years (interquartile range 0.9-5.0 years) from the date of renal biopsy, the 5-year CKD progression-free survival was 86.6% (95% CI 72.5-93.8) for the nonproteinuric group and 30.3% (95% CI 22.4-38.6) for the proteinuric group (log-rank test P < 0.001). The lower renal risk was consistent across all subgroup analyses. The all-cause mortality was also lower in the nonproteinuric group (log-rank test P = 0.005)., Conclusions: Patients with nonproteinuric diabetic kidney disease had better-controlled blood pressure and fewer typical morphological changes and were at lower risk of CKD progression and all-cause mortality., (© 2019 by the American Diabetes Association.)

Aim: The aim of this study was to assess the renal effects of the glucose-lowering SGLT2 inhibitors in Japanese type 2 diabetes mellitus patients with chronic kidney disease., Methods: The Kanagawa Physicians Association maintains a registry of patients who visit their 31 clinics. Clinical data of type 2 diabetes mellitus patients with chronic kidney disease, who were prescribed SGLT2 inhibitors in addition to other treatments, were collected and analysed., Results: SGLT2i was associated with a fall in HbA 1c from 64.1 ± 16.7 mmol/mol (8.0 ± 1.5%) to 56.5 ± 12.9 mmol/mol (7.3 ± 1.2%) ( p < 0.01) in 869 analysed cases, a decrease in urine albumin-creatinine ratio from a median of 47.1 to 41.1 mg/gCr, and decrease in estimated glomerular filtration rate from 77.7 ± 23.9 to 75.0 ± 23.9 mL/min/1.73 m 2 ( p < 0.01). The effect on albumin-creatinine ratio was independent of age or stage of estimated glomerular filtration; however, there was a significant negative correlation between albumin-creatinine ratio at the initiation of SGLT2 inhibitor and change in ACR. Multiple linear regression analysis identified use of empagliflozin, β-blockers, and sulphonylureas, Δsystolic blood pressure at office, serum Cr and albumin-creatinine ratio value at initiation of SGLT2 inhibitor as independent and significant determinants of change in ACR., Conclusions: This study confirmed that the beneficial renal effects of SGLT2 inhibitor in Japanese type 2 diabetes mellitus patients with chronic kidney disease, similar to those reported in large-scale clinical trials conducted in Western countries.