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, and 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.

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.

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.

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.

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.

Guidelines for clinical evaluation of chronic kidney disease in early stages : AMED research on regulatory science of pharmaceuticals and medical devices.

BACKGROUND: For the development of pharmaceutical products in kidney field, appropriate surrogate endpoints which can predict long-term prognosis are needed as an alternative to hard endpoints, such as end-stage kidney disease. Though international workshop has proposed estimated glomerular filtration rate (GFR) slope reduction of 0.5-1.0 mL/min/1.73 m /year and 30% decrease in albuminuria/proteinuria as surrogate endpoints in early and advanced chronic kidney disease (CKD), it was not clear whether these are applicable to Japanese patients. METHODS: We analyzed J-CKD-DB and CKD-JAC, Japanese databases/cohorts of CKD patients, and J-DREAMS, a Japanese database of patients with diabetes mellitus to investigate the applicability of eGFR slope and albuminuria/proteinuria to the Japanese population. Systematic review on those endpoints was also conducted including the results of clinical trials published after the above proposal. RESULTS: Our analysis showed an association between eGFR slope and the risk of end-stage kidney disease. A 30% decrease in albuminuria/proteinuria over 2 years corresponded to a 20% decrease in the risk of end-stage kidney disease patients with baseline UACR ≥ 30 mg/gCre or UPCR ≥ 0.15 g/gCre in the analysis of CKD-JAC, though this analysis was not performed on the other database/cohort. Those results suggested similar trends to those of the systematic review. CONCLUSION: The results suggested that eGFR slope and decreased albuminuria/proteinuria may be used as a surrogate endpoint in clinical trials for early CKD (including diabetic kidney disease) in Japanese population, though its validity and cutoff values must be carefully considered based on the latest evidence and other factors.

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.

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.

Clinical impact of suboptimal RAASi therapy following an episode of hyperkalemia.

BACKGROUND: Hyperkalemia (HK) is a barrier to optimization of renin-angiotensin-aldosterone system inhibitor (RAASi) therapy in heart failure (HF) and chronic kidney disease (CKD). We investigated cardiorenal risk associated with changes in RAASi regimen after an episode of HK in patients with HF and/or CKD. METHODS: This observational study utilized data from hospital records, claims, and health registers from the US (Optum's de-identified Market Clarity Data) and Japan (Medical Data Vision). Included patients had an index episode of HK between July 2019 and September 2021 (US), or May 2020 and September 2021 (Japan), with prior diagnosis of HF or CKD (stage 3 or 4), and RAASi use. Risk of a cardiorenal composite outcome (HF emergency visit, HF hospitalization, or progression to end-stage kidney disease) was determined in patients who discontinued RAASi, down-titrated their dose by > 25%, or maintained or up-titrated their dose following the HK episode. RESULTS: A total of 15,488 and 6020 patients were included from the US and Japan, respectively. Prior to the episode of HK, 59% (US) and 27% (Japan) of patients had achieved > 50% target RAASi dose. Following the episode of HK, 33% (US) and 32% (Japan) of patients did not fill a new RAASi prescription. Risk of the cardiorenal outcome at 6 months was higher in patients who discontinued or down-titrated versus maintained or up-titrated RAASi treatment both in the US (17.5, 18.3, and 10.6%; p <  0.001) and in Japan (19.7, 20.0, and 15.1%; p <  0.001). CONCLUSION: HK-related RAASi discontinuation or down-titration was associated with higher risk of cardiorenal events versus maintained or up-titrated RAASi.

Evaluation of Glomerular Hemodynamic Function by Empagliflozin in Diabetic Mice Using In Vivo Imaging.

BACKGROUND: Sodium glucose cotransporter 2 inhibitors may reduce kidney hyperfiltration, thereby preventing diabetic kidney disease progression, which may in turn reduce cardiovascular risk, including heart failure. However, the mechanisms that regulate renal function responses to sodium glucose cotransporter 2 inhibition are not yet fully understood. We explored the renal protective effects of sodium glucose cotransporter 2 inhibition with empagliflozin, with a focus on glomerular hemodynamic effects and tubuloglomerular feedback using in vivo multiphoton microscopy imaging techniques. METHODS: C57BL/6 mice and spontaneously diabetic Ins2+/Akita mice were studied. The mice were treated with empagliflozin (20 mg·kg-1·d-1) and insulin for 4 weeks, and the single-nephron glomerular filtration rate was measured using multiphoton microscope. A neuronal nitric oxide synthase inhibitor (7-nitroindazole, 20 mg·kg-1·d-1) or a cyclooxygenase-2 inhibitor (SC58236, 6 mg/L), or an A1 adenosine receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1 mg·kg-1·d-1) was administered to elucidate the mechanisms of tubuloglomerular feedback signaling and single-nephron glomerular filtration rate regulation. RESULTS: The urinary excretion of adenosine, nitric oxide metabolites, and the prostanoid prostaglandin E2 was also quantified. The single-nephron glomerular filtration rate in the Ins2+/Akita group was higher than in controls (C57BL/6; 4.9±1.3 nL/min versus Ins2+/Akita; 15.8±6.8 nL/min) and lower in Ins2+/Akita /empagliflozin to 8.0±3.3 nL/min (P<0.01). In vivo imaging also revealed concomitant afferent arteriolar dilation (P<0.01) and increased glomerular permeability of albumin in the Ins2+/Akita group. Empagliflozin ameliorated these changes (P<0.01). Urinary adenosine excretion in the Ins2+/Akita/empagliflozin group was higher than in Ins2+/Akita (Ins2+/Akita; 3.4±1.4 nmol/d, Ins2+/Akita/empagliflozin; 11.2±3.0 nmol/d, P<0.05), whereas nitric oxide metabolites and prostaglandin E2 did not differ. A1 adenosine receptor antagonism, but not neuronal nitric oxide synthase or cyclooxygenase-2 inhibition, blocked the effect of empagliflozin on renal function. Empagliflozin increased urinary adenosine excretion and reduced hyperfiltration via afferent arteriolar constriction, effects that were abolished by A1 adenosine receptor blockade. CONCLUSIONS: Adenosine/A1 adenosine receptor pathways play a pivotal role in the regulation of the single-nephron glomerular filtration rate via tubuloglomerular feedback mechanisms in response to sodium glucose cotransporter 2 inhibition, which may contribute to renal and cardiovascular protective effects reported in clinical trials.

Renoprotective effects of sodium-glucose cotransporter-2 inhibitors and underlying mechanisms.

PURPOSE OF REVIEW: Emerging data have demonstrated that sodium-glucose cotransporter-2 (SGLT2) inhibitors prevent cardiovascular events, especially heart failure-associated endpoints. Cardiovascular outcome trials have also suggested their renoprotective effects. One large clinical trial investigated renal primary endpoints and demonstrated that SGLT2 inhibitors slowed the progression of diabetic kidney disease (DKD). This review summarizes clinical trial data on renal outcomes and discusses potential underlying mechanisms. RECENT FINDINGS: The EMPA-REG, CANVAS, and DECLARE-TIMI 58 studies revealed that SGLT2 inhibitors reduce the risk of cardiovascular events and concomitantly suggested that these drugs slow the progression of kidney disease in type 2 diabetes. The CREDENCE trial on patients with high-risk type 2 diabetes and chronic kidney disease demonstrated that canagliflozin treatment reduced the relative risk of a composite outcome, including end-stage kidney disease, serum creatinine doubling, and renal/cardiovascular death, by 30% in these patients. Animal experiments revealed that oxidative stress, inflammation, fibrosis, and tubuloglomerular feedback are underlying renoprotective mechanisms behind SGLT2 inhibitors. SUMMARY: Recent clinical trials have established the renoprotective effects of SGLT2 inhibitors. Further investigations on mechanisms of these renoprotective effects will provide deeper insights and understanding of pathogenetic properties of DKD.

The Normalized Protein Catabolic Rate and Mortality Risk of Patients on Hemodialysis by Frailty Status: The Japanese Dialysis Outcomes and Practice Pattern Study.

OBJECTIVE: The appropriate protein intake for patients on hemodialysis complicated with frailty remains highly controversial. METHODS: We conducted a prospective cohort study using data from Japanese Dialysis Outcomes and Practice Pattern Study. The patients were separated by their baseline of normalized protein catabolic rate (nPCR) into 3 categories: low (nPCR < 1.0), medium (1.0 ≤ nPCR <1.2), and high (nPCR ≥1.2). The frailty score was calculated based on the 12-item Short Form, and frailty was defined in cases with a total score of ≥2 points. The all-cause mortality was compared between groups using a Cox proportional hazard model. RESULTS: A total of 2,404 patients were included in the longitudinal analysis, 1,096 (45.6%) of whom had frailty. Patients in the low-nPCR group showed a higher prevalence of frailty than those in the other groups. In the Cox proportional hazard model, no significant differences in the all-cause mortality were noted between the low-nPCR and medium-nPCR groups or the high-nPCR and medium-nPCR groups. Furthermore, no significant differences were noted among any groups when subjects were limited to patients with frailty. CONCLUSIONS: Patients with a low nPCR have a higher prevalence of frailty and incidence of mortality than those with a medium nPCR. Patients with a high nPCR did not show a lower survival rate than those with a medium nPCR in this study. To clarify the appropriate protein intake for patients on hemodialysis with frailty, an intervention study or large-scale, long-term cohort study will be needed.

Increased plasma plasmin-α2-plasmin inhibitor complex levels correlate with postoperative rebleeding after endoscopic surgery for spontaneous intracerebral hemorrhage.

BACKGROUND: Postoperative rebleeding (PR) is one of the most severe complications of endoscopic surgery, often performed to remove spontaneous intracerebral hemorrhage (sICH). However, the risk factors for PR remain unclear. OBJECTIVE: This study retrospectively investigated whether increased preoperative plasma plasmin-α2-plasmin inhibitor complex (PIC) levels, indicating activation of fibrinolysis, are associated with PR. METHODS: A total of 101 patients underwent endoscopic surgery to evacuate sICH at our institution from January 2010 to June 2019, and 79 patients who underwent examinations of plasma PIC levels at admission with available radiographical data were included. Correlations between PR and increased plasma PIC levels were retrospectively evaluated. RESULTS: PR occurred in eight patients (10.1%), and high PIC levels (≥ 4 or 6 µg/ml) were significantly associated with PR. The sensitivities employing high PIC levels of ≥ 4 µg/ml and ≥ 6 µg/ml were both 0.63, and the specificities using the same PIC levels were 0.86 and 0.92, respectively. Multivariable analyses showed that high plasma PIC levels of ≥ 4 µg/ml (odds ratio (OR), 12.77; 95% confidence interval (CI), 1.65-98.77; p = 0.02) or ≥ 6 µg/ml (OR, 18.33; 95% CI, 2.32-144.82; p = 0.006) were independent predictors of PR. CONCLUSIONS: This study found that increased plasma PIC levels were associated with PR following the endoscopic evacuation of sICHs, indicating that increased plasma PIC levels could be potentially used to predict PR. Further studies are needed to establish new surgical strategies and adjuvant treatments to improve surgical outcomes in patients with sICH prone to PR.

[Relationship between Coombs-positive autoimmune hemolytic anemia and development of malignant tumors: a retrospective study].

Autoimmune hemolytic anemia (AIHA) is secondary to underlying diseases, such as autoimmune diseases and lymphoid malignancies. Recently, solid cancers have also been reported to be associated with AIHA, although there is not much information available. In this study, we retrospectively examined the correlation between AIHA and onset of malignancy in 100 patients diagnosed with AIHA based on the broad definition of AIHA at our hospital and cooperating institutions from January 1, 1995 to May 31, 2016. Malignancies were detected in 52 of the 100 patients (hematological malignancies: 39 patients; solid cancers: 22 patients; total malignancies including multiple primary malignancies: 67 patients). Of the 67 patients with malignancies, 28 were diagnosed with malignancies within 6 months of AIHA diagnosis. All patients with cold agglutinin disease (CAD) were associated with malignancies. Compared with warm AIHA, solid cancers were significantly more common among the patients with CAD. These findings emphasize the importance of investigating the malignancies upon diagnosis of AIHA.

Importance of glomerular filtration rate change as surrogate endpoint for the future incidence of end-stage renal disease in general Japanese population: community-based cohort study.

BACKGROUND: Because of the necessity for extended period and large costs until the event occurs, surrogate endpoints are indispensable for implementation of clinical studies to improve chronic kidney disease (CKD) patients' prognosis. METHODS: Subjects with serum creatinine level for a baseline period over 1-3 years were enrolled (n = 69,238) in this community-based prospective cohort study in Okinawa, Japan, and followed up for 15 years. The endpoint was end-stage renal disease (ESRD). The percent of estimated glomerular filtration rate (%eGFR) change was calculated on the basis of the baseline period. RESULTS: Subjects had a mean ± SD age, 55.59 ± 14.69 years; eGFR, 80.15 ± 21.15 ml/min/1.73 m2. Among the subjects recruited, 15.81% had a low eGFR (<60 ml/min/1.73 m2) and 36.1/100,000 person years developed ESRD. Cox proportional hazards models adjusted for baseline characteristics showed that the risk of ESRD tended to be high with high rates of decrease in %eGFR changes over 2 or 3 years in the high- and low-eGFR groups. The specificities and positive predictive values for ESRD based on a cutoff value of %eGFR change of less than -30% over 2 or 3 years were high in the high- and low-eGFR groups. CONCLUSIONS: %eGFR change tends to be associated with the risk of ESRD. %eGFR change of less than -30% over 2 or 3 years can be a candidate surrogate endpoint for ESRD in the general Japanese population.

Low white blood cell count is independently associated with chronic kidney disease progression in the elderly: the CKD-ROUTE study.

BACKGROUND: Elevated white blood cell (WBC) count is a well-known predictor of chronic kidney disease (CKD) progression. However, elderly patients commonly fail to develop a high WBC count in response to several diseased states and may instead present a low WBC count. Therefore, we hypothesized that low WBC count, in addition to high WBC count, is associated with CKD progression in the elderly. METHODS: We conducted a prospective cohort study using 3-year follow-up data from the CKD Research of Outcomes in Treatment and Epidemiology study. In the present study, participants aged over 60 years with pre-dialysis CKD stages G2-G5 were eligible. Patients were stratified into three groups according to WBC count using tertiles (T). The primary outcome was a composite of end-stage renal disease and a 50% reduction in estimated glomerular filtration rate. Data were analyzed using Cox proportional hazard models with adjustments for covariates. RESULTS: We enrolled 697 patients (males, 69%). The median WBC count was 6100 cells/µl (T1, <5400, n =  222; T2, 5400-6900, n =  235; T3, ≥6900, n = 240). During a median follow-up of 868 days, the primary outcome was observed in 170 patients, whereas 54 patients died. T1 and T3 had significantly higher hazard ratios (HR) than T2 (T1, HR 1.69, 95% confidence interval 1.14-2.51; T3, HR 1.63, 95% confidence interval 1.10-2.41). Moreover, T1 had a significantly higher adjusted HR (1.54, 95% confidence interval 1.00-2.37). CONCLUSION: Low WBC count is independently associated with CKD progression in the elderly.

Continuous monitoring of blood pressure by analyzing the blood flow sound of arteriovenous fistula in hemodialysis patients.

BACKGROUND: Patients with end-stage renal disease undergoing hemodialysis (HD) have an elevated risk of cardiovascular disease-related morbidity and mortality. To prevent from such a life-threatening event, the continuous blood pressure (BP) monitoring system may contribute to detect BP decline in early stages and may help to do appropriate disposal. Our research team has introduced an electronic stethoscope (Asahi Kasei Co, Ltd., Tokyo, Japan), which translates sound intensity of Arteriovenous Fistula (AVF) to BP data using the technique of Fourier transformation that can predict continuous BP non-invasively. This study, we investigated whether electronic stethoscope-guided estimated BP (e-BP) would actually reflect systolic BP measured by sphygmomanometer (s-BP), and whether e-BP could predict fall of BP during HD. METHODS: Twenty-six patients who underwent HD treatment in our hospital were evaluated prospectively. We obtained sound intensity data from the electronic stethoscope which was equipped with the return line of HD. Then, the data were translated into e-BP data to be compared with s-BP. Correlation of total of 315 data sets obtained from each method was examined. An accuracy of diagnosis of intra-dialytic hypotension (IDH) was evaluated. RESULTS: Total of 315 data sets were obtained. A close correlation was observed between e-BP and s-BP (r = 0.887, p < 0.0001). Sensitivity and positive predictive value of predicted-BP for detection of IDH was 90 and 81.3%, respectively. CONCLUSIONS: Electronic stethoscope-guided BP measurement would be helpful for real-time diagnosis of BP fall in HD patients. Further investigations are needed.

Interventional nephrology: current status and clinical impact in Japan.

BACKGROUND: Current status and clinical significance of interventional nephrology has not been reported from Japan. METHODS: Questionnaires were mailed twice to the directors of all 534 Japanese certificated nephrology training institutions in 2014. The main questions were current performance, categorized annual procedure volume and managers of peritoneal dialysis (PD) access, vascular access (VA) surgery, endovascular intervention, and kidney biopsy. Frequencies of nephrologist involvement between high volume center and low volume center and association between the level of nephrologists' involvement to each procedure and annual procedure volume were examined. RESULTS: 332 (62.2%) institutions answered performance of all procedures and 328 (61.4%) institutions answered all procedure volume. Kidney biopsy, VA surgery, endovascular intervention and PD access surgery were performed by any doctors in 94.2, 96.3, 88.4, and 76.2% and each involvement of nephrologist was 93.9, 54.1, 53.1 and 47.6%, respectively. Cochran-Armitage analyses demonstrated significant increases in all 4 procedure volume with greater management by nephrologists (p < 0.01). Nephrologists involvement to VA surgery associated with procedure volume increase in not only VA surgery, but also PD catheter insertion (p < 0.01) and kidney biopsy (p < 0.05). And nephrologists involvement to PD catheter insertion also associated with surgical volume increase in both VA surgery (p < 0.01) and endovascular intervention (p < 0.05). CONCLUSIONS: Main manager of all 4 procedures was nephrologist in Japan. Each procedure volume increased as nephrologists become more involved. Acquisition of one specific procedure by nephrologist associated with increase not only in this specific procedure volume, but also the other procedure volume.

Observation period for changes in proteinuria and risk prediction of end-stage renal disease in general population.

AIM: Proteinuria is known to be an independent risk factor of end-stage renal disease (ESRD). But the associations between changes in dipstick proteinuria and the risk of ESRD in the general population and its appropriate observation period to predict incident ESRD are unknown. METHODS: We assessed the changes in dipstick proteinuria in 69 021 participants aged ≥20 years who participated in health check-ups from 1993 and more than once until 1996 in Okinawa, Japan. Development of ESRD until 2011 was identified using dialysis registry. Cox proportional hazards model and receiver operating characteristic (ROC) curve were used. RESULTS: At baseline, proteinuria (±) and ≥(1+) were observed in 2.4% and 1.2% of total subjects. 1.5% of subjects had decreased and 9.4% of subjects had increased their proteinuria level after 2 years. After adjustment for confounding factors, hazard ratios (95% confidence interval) of ESRD for subjects with proteinuria change ≤ - 1, +1, +2, +3, and +4 level during 2 years compared to subjects with no change were 0.89 (0.43-1.87), 3.18 (2.21-4.60), 8.01 (5.55-11.55), 11.17 (6.59-19.95), and 16.59 (5.95-46.25), respectively. Heterogeneity existed between changes in proteinuria level during 1 or 3 years and the risk of ESRD among baseline proteinuria. Area under the ROC curve (95%CI) to predict ESRD by increase in proteinuria level during 1, 2, and 3 years were 0.650 (0.623-0.679), 0.779 (0.751-0.808), and 0.778 (0.748-0.808), respectively. CONCLUSIONS: The changes in dipstick proteinuria were an independent predictor of ESRD in the general population. Changes in proteinuria over 2 years may be appropriate for the risk prediction of ESRD.

Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study.

BACKGROUND: Recent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors can potentially reduce the risk of cardiovascular mortality in patients with type 2 diabetes mellitus (T2DM). However, there is little or no information on the therapeutic effects of SGLT2 inhibitors on the progression of atherosclerosis. This dapagliflozin effectiveness on vascular endothelial function and glycemic control (DEFENCE) study was designed to determine the effects of dapagliflozin, a SGLT2 inhibitor, on endothelial function in patients with early-stage T2DM. METHODS: DEFENCE is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial. Between October 2015 and August 2016, 80 T2DM patients treated with 750 mg of metformin (hemoglobin A1c ≥6.0 and <8.0%, n = 80) were enrolled and randomized to receive either 1500 mg/day metformin (the metformin group, n = 40), or 750 mg/day metformin supplemented with 5 mg/day dapagliflozin (the dapagliflozin group, n = 40), for 16 weeks. The primary endpoint was a change in flow-mediated dilation (FMD) from baseline to the end of the 16-week treatment period. The secondary outcomes include changes in indexes of glycemic control, lipid metabolism, and oxidative stress, body composition, and safety evaluation. RESULTS: Although FMD tended to improve only in the dapagliflozin group, ΔFMD was comparable between the two groups. Analysis of patients with HbA1c >7.0% showed significant improvement of FMD in the dapagliflozin group than metformin group (P < 0.05). HbA1c, fasting plasma glucose, plasma glucagon, and body weight significantly decreased in both groups. Interestingly, urine 8-hydroxy-2'-deoxyguanosin, a biomarker of oxidative stress, was significantly lower in the dapagliflozin group than metformin group at 16 weeks (P < 0.001). CONCLUSIONS: Dapagliflozin add-on therapy to metformin for 16 weeks improved endothelial function, as assessed by FMD, in patients with inadequately controlled early-stage T2DM. Improvement in oxidative stress may contribute to the improvement in FMD. Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000018754).