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Responsiveness to erythropoiesis-stimulating agents (ESAs) has been reported to be associated with increased cardiovascular disease (CVD) and mortality in patients undergoing hemodialysis (HD). However, the association between hyporesponsiveness to the long-acting ESA, epoetin beta pegol (CERA), and CVD remains unknown.This multicenter prospective study included 4034 patients undergoing maintenance HD. After shifting from prior ESA to CERA, we studied the association between erythropoietin resistance index (ERI) at six months and outcomes, including cardiac events, major adverse cardiovascular events (MACE), and all-cause mortality, using Cox proportional hazards models (Landmark analyses) and marginal structural models to adjust for time-dependent confounding factors, including iron-containing medications and hemodiafiltration (HDF).The median dialysis vintage and the observational period were 5.0 years and 22.1 months, respectively. The landmark analyses revealed that the highest tertile of baseline ERI (T3) was associated with a significantly higher all-cause mortality than the lowest tertile (T1) (hazard ratio [HR]: 1.48, 95% CI: 1.03-2.13). Furthermore, marginal structural models revealed that time-dependent ERI T3 was significantly associated with increased cardiac events (HR: 1.59, 95% CI: 1.14-2.23), MACE (HR: 1.60, 95% CI: 1.19-2.15), all-cause mortality (HR: 1.97, 95% CI: 1.40-2.77), and heart failure (HF) (HR: 2.05, 95% CI: 1.23-3.40) compared to T1. A linear mixed effects model showed that iron-containing medications and HDF are negatively associated with time-dependent ERI.Baseline ERI at six months predicted only all-cause mortality; however, time-dependent ERI was a predictor of cardiac events, all-cause mortality, MACE, and HF. The widespread use of iron-containing medications and HDF would ameliorate ESA hyporesponsiveness.

Although multidisciplinary care (MDC) is necessary for controlling chronic kidney disease (CKD), its impact on compliance with management target values in the CKD guidelines remains unclear. This study was designed to clarify the relationship between compliance with management target values and renal prognosis in CKD outpatients who received MDC.There were 255 outpatients with pre-dialysis CKD who received MDC. Achievement rates of systolic, and diastolic blood pressure, hemoglobin, uric acid, low-density lipoprotein cholesterol, and hemoglobin A1c values determined according to CKD guidelines were compared before and 12 months after MDC. In addition, after dividing achievement rates of the target values at 12 months after MDC into four groups (A 30% ≤ B 60% ≤ C 80% ≤ D), dialysis initiation and renal survival rates were compared.There was a significant increase in the overall achievement rate from 62.8 to 69.1% (p 0.001). The higher the achievement rate after MDC, the lower the dialysis initiation rate (A 72.7%, B 35.3%, C 20.5%, D 8.2%, p 0.001). There was also a significantly higher renal survival rate (p 0.001). These findings suggest that MDC for CKD raised awareness of health literacy, and improved the achievement rate of target values. Furthermore, the higher the achievement rate, the later the initiation of dialysis, which led to improvement of renal survival.MDC can improve compliance with management target values for CKD, suggesting that it may improve renal prognosis.

Background Previous studies have shown that hyponatremia is associated with greater mortality in hemodialysis (HD) patients. However, there have been few reports regarding the importance of the change in serum sodium (SNa) concentration (ΔSNa) during dialysis sessions. To investigate the relationships of pre-dialysis hyponatremia and ΔSNa during a dialysis session with mortality, we analyzed data from a national registry of Japanese patients with end-stage kidney disease. Methods We identified 178,114 patients in the database who were undergoing HD 3 times weekly. The study outcome was 2-year all-cause mortality, and the baseline SNa concentrations were categorized into quintiles. We evaluated the relationships of SNa concentration and ΔSNa with mortality using Cox proportional hazards models. Results During a 2-year follow-up period, 25,928 patients died. Each 1-mEq/l reduction in pre-HD SNa concentration was associated with a cumulatively greater risk of all-cause mortality (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.05–1.06). In contrast, a larger ΔSNa was associated with higher all-cause mortality (HR for a 1-mEq/l increase in ΔSNa, 1.02; 95% CI 1.01–1.02). The combination of low pre-HD SNa concentration and large ΔSNa was also associated with higher mortality (HR 1.09; 95% CI 1.05–1.13). Participants with the lowest SNa concentration (≤136 mEq/L) and the highest ΔSNa (>4 mEq/L) showed higher mortality than those with an intermediate pre-HD SNa concentration (137–140 mEq/L) and the lowest ΔSNa (≤2 mEq/L). Conclusions Lower pre-HD SNa concentration and higher ΔSNa are associated with a greater risk of mortality in patients undergoing HD., Graphical abstract

Background/Aims: There is lack of definitive evidence about the association between erythropoiesis-stimulating agent (ESA) responsiveness in the pre-dialysis phase and mortality. Therefore, we conducted a hospital-based, retrospective, cohort study to assess the predictive value of ESA response for prognosis in incident hemodialysis patients. Methods: A total of 108 patients without preexisting cardiovascular disease who had been started on maintenance hemodialysis were studied. ESA responsiveness just before starting dialysis was estimated using an erythropoietin resistance index (ERI). The endpoint was defined as all-cause death. Results: During a mean follow-up period of 3.1 ± 1.6 years, 18 (17%) patients died. Overall, the multivariate Cox regression analysis revealed that the log-transformed ERI remained an independent predictor of all-cause death after adjustment using a propensity score (hazard ratio 2.25, 95% CI 1.25–4.06). Conclusions: Among incident hemodialysis patients, hyporesponsiveness to ESA may be associated with mortality.

The traditional anion gap (AG) equation is widely used, but its misdiagnosis in end-stage kidney disease (ESKD) patients has not been investigated fully. Diagnostic accuracy to detect high AG was cross-sectionally evaluated using 3 AG equations in 1733 ESKD patients with an eGFR less than 15 mL/min/1.73 m2. The prevalence of high AG was 67.9%, 92.1% and 97.4% by the traditional, albumin-adjusted AG (aAG) and full AG equations, respectively. The sensitivity, specificity, accuracy and Kappa coefficient obtained with the traditional AG vs aAG equation were 0.70 vs 0.94, 0.98 vs 0.93, 0.7 vs 0.94, and 0.103 vs 0.44, respectively. Next, we created a subcohort comprising only patients with high full AG and investigated how the traditional AG equation leads to misdiagnoses. Multivariable-adjusted regression analysis in 1688 patients revealed that independent factors associated with a false-negative AG diagnosis were ARB use, eGFR, blood leukocyte count, serum chloride, bicarbonate, ionized calcium, potassium, albumin and phosphate. 93.2% of our subcohort prescribed any of RAAS inhibitors, Loop diuretics or Alkali which could increase either serum chloride or bicarbonate. Frequent use of these possible AG-reducing medications may conceal high AG state in patients with ESKD unless they have incidental inflammation which may increase AG value.

The aim of comprehensive multidisciplinary care (MDC) by the chronic kidney disease (CKD) team is not only to prevent worsening renal function, but also provide education on the selection of renal replacement therapy (RRT) by shared decision making (SDM). The purpose of this study was to examine the effects of MDC for predialysis outpatients on dialysis therapy, especially with regard to peritoneal dialysis (PD). This study evaluated 112 CKD patients who underwent dialysis at our hospital starting from 2012, with 53 outpatients receiving MDC from the CKD team and 59 outpatients not receiving MDC. Annual decreases in the estimated glomerular filtration rates (ΔeGFR), the duration from the time of intervention to dialysis initiation, the urgent dialysis rate using a temporary catheter, and the PD selection rate were compared and examined between the two groups. The ΔeGFR, the duration from intervention to PD initiation, and the PD retention rate were compared between 18 PD patients in the MDC group and 10 PD patients in the non-MDC group. The MDC group had a significantly lower ΔeGFR, significantly longer duration, and a significantly lower urgent dialysis initiation rate versus the non-MDC group. Moreover, there was a significantly higher PD selection rate, significantly prolonged duration, and significantly higher PD retention rate. Multidisciplinary CKD team care for outpatients is effective in delaying the progression of CKD and avoiding the initiation of urgent dialysis; contributing to improved PD selectivity and continuity by SDM.

Recent studies have reported that high mean corpuscular volume (MCV) might be associated with mortality in patients with advanced chronic kidney disease (CKD). However, the question of whether a high MCV confers a risk for mortality in Japanese patients remains unclear. We conducted a longitudinal analysis of a cohort of 8571 patients using data derived from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS) phases 1 to 5. Associations of all-cause mortality, vascular events, and hospitalization due to infection with baseline MCV were examined via Cox proportional hazard models. Non-linear relationships between MCV and these outcomes were examined using restricted cubic spline analyses. Associations between time-varying MCV and these outcomes were also examined as sensitivity analyses. Cox proportional hazard models showed a significant association of low MCV (

Background and Aims Hemodialysis (HD) patients hyporesponsive to erythropoiesis stimulating agents (ESAs) were reported to have poor prognosis. However, little is known regarding the association between the hyporesponsiveness to CERA and the types of outcome in HD patients. Moreover, the effect of on-line HDF on hyporesponsiveness to CERA has not been evaluated so far. Method In this multicenter prospective study, we enrolled 4034 maintenance HD patients receiving any kinds of ESA. Prior ESA was changed to CERA in all patients. We studied the association between erythropoietin resistance index (ERI) at 6-month after the change to CERA (baseline ERI) and such outcomes as cardiovascular events and/or mortality using Cox proportional hazards models (landmark analyses). ERI was defined as monthly CERA dose divided by hemoglobin and dry weight. Just before the enrollment of the patients, iron-based phosphate binders became available and on-line hemodiafiltration (HDF) began to be reimbursed in Japan, therefore, we examined whether oral iron-containing drugs and on-line HDF had some effects on the serial trend of ERI by mixed effects model with time-dependent ERI as a dependent variable. When ERI is found to be improved by these changes in practice patterns, we further studied the effect of time-dependent ERI on such outcomes as cardiovascular events, mortality, death due to cancer, and death due to infection by using marginal structural models to eradicate time-dependent confounding by iron parameters, C-reactive protein, iron-containing drugs, and HDF. Missing values were imputed by multiple imputations. Results Mean age was 65.9 years and 43.1% of patients had diabetes. The median dialysis vintage and observation period was 5.0 years and 22.1 months, respectively. The percentage of patients receiving oral iron-containing drugs increased from 11.1% at baseline to 25.0% at 24-month. As a result, mean TSAT level increased from 24.5% to 27.4% at 24-month. The percentage of patients on on-line HDF also increased from 13.5% to 22.6%. ERI gradually decreased as time went by with great improvement especially in patients with highest quintile of ERI (Q5). Mixed effects model with time-dependent ERI as a dependent variable showed that introduction of iron-containing drugs and on-line HDF had improved ERI significantly. The landmark analyses including 3001 patients failed to show significant associations between baseline ERI quintile and cardiovascular events or mortality. We only found that highest quintile of baseline ERI (Q5) was associated with significantly higher composite events of mortality and cardiovascular events as compared to the lowest quintile (Q1) (Hazard ratio [HR], 1.56; 95% CI; 1.04-2.32). However, marginal structural models showed that time-dependent ERI Q5 was significantly associated with higher cardiovascular event rate as compared to Q1 (HR, 2.11; 95% CI; 1.31-3.38). Trend toward higher rate of mortality with the increase in time-dependent ERI quintile was also observed (HR of Q5, 3.07; 95% CI; 1.95-4.83). Similar but stronger relationships were observed for death due to infection (HR of Q5, 6.70; 95% CI; 1.89-23.77) and death due to cancer (HR of Q5, 15.08; 95% CI; 4.08-55.74). Conclusion The prevailing use of iron-containing drugs and on-line HDF has improved hyporesponsiveness to CERA in Japan. Therefore, baseline ERI at 6-month did not predict subsequent cardiovascular events or death. However, high time-dependent ERI was a predictor of cardiovascular events, death due to infection, and death due to cancer as well as all-cause mortality. Strong association of time-dependent ERI was observed especially with death due to cancer.

Background and Aims There are several reports showing on the relationship between electrocardiographic (ECG) findings and prognosis in dialysis patients. We recently reported that among various ECG findings, T-wave of lead aVR (aVRT) amplitude revealed the strongest and significant association with cardiovascular disease (CVD) events and all-cause mortality in prevalent dialysis patients (Ther Apher Dial, 2017). We also reported that BNP level was significantly associated with CVD-related mortality and all-cause mortality in our cohort study (Ren Fail, 2018; Sci Rep, 2019). On the other hand, BNP levels have been reported to be higher among elderly and women and lower in people with higher body mass index. However, there is no report showing the correlation between NT-proBNP and ECG findings. Method From our Miyazaki Dialysis Cohort, we extracted patients who had both ECG findings and NT-proBNP data and did not have atrial fibrillation. We examined the relationship between log NT-proBNP level and various ECG findings using Spearman analysis as a cross-sectional study. Results We analyzed 519 hemodialysis patients (44.1% women, mean age was 66.1 years old, median dialysis vintage was 105 months) without atrial fibrillation. Diabetes mellitus was the underlying disease in 25.0% and a history of CVD was found in 25.2% of all patients. Median and IQR (25-75 percentile) of NT proBNP was 4150 (1980-8960). Log NT-proBNP level was significantly correlated with aVRT magnitude (mV), electrical left ventricular high voltage (mV), QTc time (ms), and T-wave amplitude of I lead (mV) (r=0.289, p Conclusion Although some ECG findings and BNP level are factors associated with CVD events and death, there was also a significant correlation between these two factors. There has been no report showing the relationships between these two factors, and it may be useful in considering BNP levels in dialysis patients.

Despite the advances in management, acute decompensated heart failure (ADHF) continues to be associated with poor clinical outcomes. Renal dysfunction, especially acute kidney injury (AKI), is one of the strongest predictors of adverse outcomes in ADHF. The association between the heart and the kidney in patients with ADHF is complex, and a complete understanding of this bidirectional interaction has not been elucidated. There are two big issues in this field. First is that many different definitions for renal dysfunction have been used conventionally. This would create different interpretations of renal failure in ADHF. Another problem is that the timing of WRF/AKI onset during hospitalization varies. To reconsider the future direction of AKI, this review focused on the current perspectives on AKI in ADHF patients.

Comprehensive education about lifestyle, nutrition, medications and other types of treatment is important to prevent renal dysfunction in patients with chronic kidney disease (CKD). However, the effectiveness of multidisciplinary care on CKD progression has not been evaluated in detail. We aimed to determine whether multidisciplinary care at our hospital could help prevent worsening renal function associated with CKD. A total of 150 pre-dialysis CKD outpatients accompanied (n = 68) or not (n = 82) with diabetes mellitus (DM) were enrolled into this study. We assessed annual decreases in estimated glomerular filtration rates (ΔeGFR), and measured systolic blood pressure (SBP), diastolic blood pressure (DBP), hemoglobin (Hb), uric acid (UA), low-density lipoprotein cholesterol (LDL), hemoglobin A1c (HbA1c) values and urinary protein to creatinine ratios (UPCR) 12 months before and after multidisciplinary care. In addition, changes in the number of medications and prescription ratio before and after multidisciplinary care were assessed in 90 patients with CKD who could confirm their prescribed medications. The ΔeGFR significantly improved between before and after multidisciplinary care from − 5.46 to − 0.56 mL/min/1.73 m2/year, respectively. The number of medications and prescription ratio showed no significant changes before and after multidisciplinary care. The ratios of improved ΔeGFR were found in 66.7% of all patients, comprising 63.1% of males and 76.9% of females, 64.8% without DM and 69.4% with DM. Values for UA, LDL, and HbA1c were significantly reduced among patients with improved ΔeGFR. Comprehensive multidisciplinary care of outpatients might help prevent worsening renal function among patients with CKD.

There is no obvious evidence regarding biological variation of procalcitonin (PCT) levels in hemodialysis (HD) patients without infections. The aim of this study was to determine the within- and between-person biological variation of PCT levels in HD patients without infections. A multicenter, prospective, cohort study enrolled 123 HD patients without any signs of infectious disease. Baseline PCT levels were determined pre- and post-HD, and then repeated pre-HD PCT measurements were performed at 2, 4, 8, 12, 16, 20, and 24 weeks after baseline blood-sampling, regardless of the presence or absence of infectious disease. Analytical variation (CVa), the within-person biological variation (CVi), between-person biological variation (CVb), individual index (II), and the reference change value (RCV) were calculated. The mean age was 62.4 years, 76.4% were male, and 32.5% had diabetes. The mean duration of HD was 87 months. The median value for baseline pre-HD PCT was 0.23 ng/mL, which is much higher than the reference level for healthy individuals. PCT levels decreased of 46.6% after a single HD session. CVi was 24.9%, CVb was 54.2%, II was 0.46, and RCV was calculated as 96.4% with 99% probability. The PCT level was significantly higher in stable HD patients without manifest bacterial infection. CVb was more variable than CVi in HD patients, which indicates that relative change is more important than absolute PCT levels for diagnosing bacterial infection, and doubling or more of the baseline PCT level may imply the presence of a bacterial infection in HD patients.

Fluid volume overload is common and is associated with adverse outcomes in hemodialysis patients. Practicing physicians individually manage fluid volume balance in their dialysis patients according to blood pressure, interdialytic weight gain, cardiac function, nutritional status, and other comorbidities. However, accurate assessment of fluid volume status remains a concern. Indicators of dry weight target have been explored further with newer concepts and technologies. In general, total body water comprises approximately 50%-60% of adult body weight (range, 45%-75%), and water comprises 73.3% of lean body mass. The standard hydration status between intracellular water and extracellular water is maintained at a ratio of 62:38 in healthy adults, which, however, is influenced universally by body cell volume driven by age and muscle mass. Fluid volume imbalance in dialysis patients also is characterized primarily by decreased body cell mass associated with aging and muscle attenuation, as well as excess extracellular water content associated with sodium retention, which may be associated with the reserve capacity for volume overload. Indeed, dialysis patients with a leaner body mass have a higher prevalence of hypertension, poorer hypertension control, and greater left ventricular hypertrophy. Understanding of these body composition changes by aging and sarcopenia can aid clinical decision making in the dry weight assessments in dialysis patients. Advising patients with consistently high interdialytic weight gain to practice salt restriction and providing appropriate nutritional support for malnourished patients with downward trajectory in their dry weight would be of great help to achieve optimal fluid volume status.

The fluid volume balance between intracellular water (ICW) and extracellular water (ECW) gradually changes with age and various medical conditions. Comprehension of these physiological changes would aid in clinical decision-making related to body fluid assessments. A total of 1,992 individuals (753 men and 1,239 women) aged ≥15 yr included in this study had their body composition measurements performed at training gyms in 2014. We developed a regression formula to assess the association of age with the ratio of ECW to ICW in these subjects. The mean ages of male and female subjects were 51.2 ± 15.2 and 57.4 ± 15.2 yr, and their mean body mass indexes were 23.4 ± 3.3 and 21.1 ± 2.8 kg/m2, respectively. The total fluid volumes of male and female subjects were 39.6 ± 4.9 and 27.7 ± 3.0 liters, whereas the percent body fat mass per kilogram of body weight were 19 and 26%, respectively. The ECW-to-ICW ratio increased with age because of the steeper decrease in the ICW content than in the ECW content, especially after the age of 70 yr. The regression formulas used for calculating the age-adjusted ECW/ICW ratio were as follows: 0.5857 + 7.4334 × 10−6 × (age)2 in men and 0.6062 + 5.5775 × 10−6 × (age)2 in women. In conclusion, the fluid imbalance between ICW and ECW contents is driven by decreased cell volume associated with aging and muscle attenuation. Therefore, our proposed formula may serve as a useful assessment tool for the calculation of body fluid composition.

Thallium-201 washout rate of stress myocardial perfusion imaging (MPI) has been reported to correlate with coronary flow reserve which is a parameter of myocardial microcirculation. However, the evidence for its use in diabetic kidney disease (DKD) has been lacking, and the association between thallium-201 washout rate and adverse outcomes including death is unknown. Therefore, the present study was conducted to evaluate the predictive ability of thallium-201 washout rate for mortality in DKD patients initiating hemodialysis. A total of 96 patients with type 2 diabetes who had been started on maintenance hemodialysis undergoing stress MPI with thallium-201 within 1 year, 72 men and 24 women, with a median age of 67 years, were studied. The endpoint was defined as all-cause death. The Cox proportional hazards model was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). During the mean follow-up period of 3.4 ± 2.1 years, 18 (18.8%) deaths occurred. Cumulative survival rates during the follow-up period, with thallium-201 washout rate levels in the lowest tertile (3.1–36.2%), the middle tertile (36.5–46.3%), and the highest tertile (46.4–66.2%), were 51.0, 86.5, and 85.3%, respectively. Overall, the multivariate Cox regression analysis revealed that thallium-201 washout rate remained an independent predictor of death after adjusting by confounding variables (HR 0.91, 95% CI 0.85–0.97). Among DKD patients initiating hemodialysis, thallium-201 washout rate seems to be useful for predicting death.

In dialysis patients, electrocardiogram (ECG) abnormalities are common. However, the associations between the T-wave of the lead aVR (aVRT) amplitude and cardiovascular (CV) events or total mortality are unknown. We performed a prospective, observational cohort study of prevalent hemodialysis patients (N = 474), followed for 4 years. Outcomes were composite CV events and all-cause mortality. Predictors were baseline aVRT and other ECG findings. ECG parameters were analyzed in three models: model 1, univariate; model 2, basic adjustments; and model 3, model 2 plus serum albumin, C-reactive protein level, and NT-proBNP. By Cox analysis, aVRT was best associated with both endpoints through model 1 to 3 compared to other ECG findings. Patients categorized according to aVRT amplitude showed a step-by-step increase in hazard ratios for both endpoints. The aVRT amplitude level was significantly associated with not only composite CV events but also with all-cause mortality in prevalent dialysis patients.

The mineral bone disorder of CKD, called Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), has a major role in the etiology and progression of cardiovascular disease in CKD patients. Since the main emphasis in CKD-MBD is on three categories (bone abnormalities, laboratory abnormalities, and vascular calcifications), we have routinely accepted ectopic cardiovascular calcifications as a central risk factor in the pathophysiology of CKD-MBD for cardiac events. However, recent compelling evidence suggests that some CKD-MBD-specific factors other than vascular calcification might contribute to the onset of cardiovascular disease. Most notable is fibroblast growth factor-23 (FGF23), which is thought to be independently associated with cardiac remodeling. Slow progression of cardiac disorders, such as vascular calcification and cardiac remodeling, characterizes cardiac disease due to CKD-MBD. In contrast, fatal arrhythmia may be induced when QT prolongation occurs with CKD-MBD treatment, such as with lower Ca dialysate or the use of calcimimetics. Sudden onset of fatal cardiac events, such as heart failure and sudden cardiac death, due to fatal arrhythmia would be another distinctive phenomenon of CKD-MBD. This may be defined as CKD-MBD-specific cardiac complex syndrome.

We challenged to identify the cutoff value of cTnT in chronic kidney disease (CKD) patients by point of care assessment way. A single center, prospective cross-sectional study was planned and performed. 201 consecutive patients who were visited emergency room for chest symptoms were enrolled in this study. All patients were performed routine practice for differential diagnosis of chest symptom by cardiologist. Simultaneously, semiquantitative measurement of cTnT was performed using same blood sampling on the blind condition to cardiologists for this study. Study patients were divided into four groups according to the estimated glomerular filtration rate (eGFR), CKD1-2, CKD3, CKD4-5, and CKD5D. Usefulness of semiquantitative measurement for diagnosing ACEs was investigated in each group. 77 (38%) of total patient was diagnosed as acute coronary events (ACEs). About 50% of patients were showing cTnT level less than 0.03 ng/mL. The cTnT level over 0.1 ng/mL was found in 30% of total subjects. Mean quantitative value of cTnT was 0.29 ± 0.57 ng/mL in total subjects. Estimated cutoff value in CKD3 patients was 0.088 ng/mL with a sensitivity of 59.3% and specificity of 80.0%. Interestingly, the cutoff values of CKD1-2, CKD4-5, and CKD5D were 0.047, 0.18, and 0.27 respectively, which are half, two times, and three times of CKD3 cutoff value 0.088. The specificities of four cutoff values in each CKD group were showing over 80%, which is higher than sensitivity, respectively. In CKD patients, semiquantitative, point of care assessment of cTnT could be a useful tool for screening for ACEs.

Background Nausea is a major uremic symptom and a frequent indication for starting dialysis. However, preventive medication for uremic nausea has not yet been identified. Vitamin D receptor activators (VDRAs) may prevent uremic nausea via their pleiotropic actions. The objective of this study was to explore whether VDRA administration during the predialysis period is associated with a reduced prevalence of uremic nausea just prior to beginning dialysis. Methods A multicenter, retrospective, cross-sectional study was performed to identify a medication to prevent uremic nausea. Patients with stage 5 CKD who were followed-up over 3 months were included. The primary outcomes examined were the prevalence of uremic nausea, congestive heart failure (CHF), and intractable edema at dialysis commencement. The predictor variable was VDRA use during the predialysis period. Results One thousand five hundred and thirty six patients who had just begun dialysis in nine Japanese facilities between January 2006 and October 2013 were included. Two hundred and thirty (15.0%) patients had commenced dialysis because of uremic nausea, and three hundred and ninety two (25.5%) patients had been using VDRAs before initiating dialysis. Logistic regression analysis showed that, among the medications examined in this study, only VDRA use was independently associated with a lower frequency of uremic nausea (OR 0.512, 95% CI 0.347–0.738, P = 0.0003). On the other hand, CHF and intractable edema were not associated with VDRA administration. Conclusion Use of VDRAs during the predialysis period was the only factor associated with a lower prevalence of uremic nausea, suggesting that VDRAs may prevent uremic nausea in patients with advanced CKD.

Although the mechanism of the cardio-renal anaemia syndrome (CRAS) has been elucidated in considerable detail over the past decade, cardiovascular disease (CVD) remains a leading cause of death among patients with end-stage kidney disease (ESKD) undergoing haemodialysis, and these patients' cardiovascular mortality is greater than that of the general population. Recent studies have reported that the CVD risk increases with advancing chronic kidney disease (CKD) stage. Furthermore, the incidence of cardiovascular events is highest during the first week after dialysis initiation, with increased risk in incident haemodialysis patients. This accumulated evidence demonstrates that how patients are managed during the pre-dialysis phase may have important implications on long-term outcomes in ESKD. Anaemia, a non-traditional risk factor for CVD, advances exponentially along with declining kidney function due to insufficient erythropoietin production. Anaemia causes functional abnormalities of the heart, as represented by cardiac hypertrophy, which results from increased cardiac workload induced by an increased preload. Left ventricular hypertrophy (LVH), a traditional risk factor for CVD, is especially associated with advanced CKD stage and could be a major risk factor for cardiovascular complications such as ischaemic heart disease, heart failure, and sudden cardiac death. In ESKD, anaemia develops more severely and requires a higher amount of erythropoiesis-stimulating agent (ESA) therapy before dialysis initiation. This suggests that improvement in anaemia management during the pre-dialysis phase may have a beneficial effect on cardiac hypertrophy and contribute to reducing the CVD risk after initiating haemodialysis.

Patients with high serum ferritin and low transferrin saturation (TSAT) levels could be considered as presenting with dysutilization of iron for erythropoiesis. However, the long-term safety of iron administration in these patients has not been well established. An observational multicenter study was performed over 3 years. In 805 patients undergoing maintenance hemodialysis (MHD), we defined dysutilization of iron for erythropoiesis in patients with lower TSAT (

Recent lines of evidence suggest that, as in other countries, sudden cardiac death (SCD) is more common in the Japanese dialysis clinical setting than we previously thought.Three specific important findings may underlie the increased incidence of SCD in dialysis patients. Even after successful coronary revascularization, hemodialysis (HD) patients continue to have a higher incidence of SCD than the general population. Second, about 70% or more of end-stage kidney disease patients have concentric and eccentric left ventricular hypertrophy, which predisposes many dialysis patients to interstitial fibrosis, decreased coronary perfusion reserve, and decreased ischemia tolerance. Third, mildly impaired left ventricular dysfunction, with an ejection fraction50%, is associated with a greater risk of SCD in dialysis patients. We have believed and accepted a common sense theory that paroxysmal ventricular tachycardia and fibrillation are the central cause of SCD in HD patients, because such cardiac functional morphological abnormalities were observed, and there are many chances for ventricular arrhythmia triggers, such as volume expansion and electrolyte shift, to develop. However, the type of fatal arrhythmia responsible for SCD differs between before and after HD. Sudden cardiac arrest (SCA) from ventricular fibrillation (VF) was more often seen in the post-HD setting, while SCA from non-VF, which may be bradyarrhythmia, was more often seen in the pre-HD setting. This may imply that the causes of SCA are bradyarrhythmia due to hyperkalemia in the pre-HD setting on the day after a long interval, and fatal ventricular arrhythmia due to a prolonged QT interval in the post-HD setting, because some recent evidence suggests that shifts of electrolytes, such as potassium and calcium, during HD cause rapid prolongation of the QT interval after HD, which may lead to the onset of ventricular arrhythmia and SCD. In fact, a higher calcium gradient, defined as the difference between the pre-HD corrected total serum calcium level and the dialysate calcium level, was associated with a higher risk of SCD in HD patients. Key Messages: Further study is needed to determine which combination of calcium, potassium, and bicarbonate concentrations in dialysate is optimal to avoid SCD in high-risk HD patients.

Objectives Patients with end-stage renal disease (ESRD) treated with hemodialysis suffer a high burden of poor functional status. Poor functional status is known as a strong, consistent predictor of mortality. However, little is known about the trajectory of functional status and its association with clinical outcomes in the ESRD population. We examined the association between a change in the functional status over time and all-cause mortality among patients on hemodialysis. Design and methods This was a prospective cohort study of 817 patients with ESRD on hemodialysis with repeat measures of functional status, who enrolled in the Japan Dialysis Outcomes and Practice Patterns Study phase V. The functional status was assessed based on the Katz Index and Lawton-Brody instrumental activities of daily living scale, and the assessments were conducted twice over a median of 361 (range: 339–378) days between 2012 and 2013. We classified patients into 2 groups based on having or not having at least a 1-point decline in the functional status score. To evaluate the association between the decline in the functional status and all-cause mortality with adjustment for potential confounders, a Cox regression analysis was conducted. Results Over the study period, 19.9% of the patients showed a decline in the functional status score. During the follow-up period, 44 (5.4%) patients died. Using the Cox regression analysis and adjusting for potential confounders, it was determined that the decline in functional status score was significantly associated with higher mortality (incidence rate: 2.2 vs. 7.0 per 100 person-years; adjusted hazard ratio: 2.68; 95% confidence interval: 1.31-5.50). Conclusions The present study provides evidence that ESRD patients on hemodialysis demonstrating a decline in the functional status are at elevated risk of mortality. Our findings strengthen the evidence underpinning the importance of interventions to maintain the functional status in this vulnerable population.

BACKGROUND Recent lines of evidence suggest that, as in other countries, sudden cardiac death (SCD) is more common in the Japanese dialysis clinical setting than we previously thought. SUMMARY Three specific important findings may underlie the increased incidence of SCD in dialysis patients. Even after successful coronary revascularization, hemodialysis (HD) patients continue to have a higher incidence of SCD than the general population. Second, about 70% or more of end-stage kidney disease patients have concentric and eccentric left ventricular hypertrophy, which predisposes many dialysis patients to interstitial fibrosis, decreased coronary perfusion reserve, and decreased ischemia tolerance. Third, mildly impaired left ventricular dysfunction, with an ejection fraction

High prevalence of iron deficiency (ID) and cardiomyopathy have been observed in patients with end-stage kidney disease (ESKD). Our objective was to clarify associations between ID and cardiac remodeling in patients with ESKD.A cross-sectional study was conducted using 1974 Japanese patients with ESKD at the initiation of maintenance dialysis. Levels of hemoglobin (Hb), iron status, and cardiac enlargement as assessed by the cardiothoracic ratio (CTR) were determined immediately before the first hemodialysis session. Circulatory ID was defined as transferrin saturation (TSAT) 20%, and stored ID was defined as ferritin level100 ng/dL.The mean age was 67 years. Median CTR was 54.0%. The prevalence of circulatory and stored ID was found to be 38% and 34%, respectively. CTR was higher in patients with circulatory ID than in those without. Even in ESKD patients without overhydration, significant negative association was observed between TSAT and CTR. Higher odds ratios in parallel with higher CTR categories compared with the reference category of CTR45% were found in patients with TSAT20% on multinomial analysis, but ferritin did not show any significant associations. The odds ratio for CTR54% showed an upward trend in patients with TSAT20% (odds ratio: 1.3) and10% (odds ratio: 1.6) compared with the reference, even after adjusting for confounding variables such as Hb and ferritin. However, that phenomenon was eliminated by adding usage of an iron agent.Circulatory ID is closely associated with an enlarged heart independent of ferritin and Hb. Iron supplementation in the predialysis phase of chronic kidney disease may prevent cardiac remodeling independent of Hb level in patients chronic kidney disease.

Objective Therapies for chronic kidney disease have changed greatly over the last decade. The aim of this study was to examine the changes in the clinical characteristics and carotid atherosclerosis of patients with end-stage kidney disease (ESKD) over the last 9 years. Methods A cross-sectional study of 150 consecutive patients with ESKD who had initiated maintenance dialysis between January 2005 and December 2013 was conducted. The patients' mean age was 68 ± 13 years. The group comprised 73% men, and 63% of the patients had diabetic nephropathy. The carotid artery-intima media thicknesses and the plaque scores (PS) were measured using carotid artery ultrasonography within 3 months of dialysis initiation. Changes in the patients' carotid atherosclerosis and clinical characteristics over the years were examined by categorizing the patients into 3 groups representing 3-year intervals based on when dialysis was initiated. Results The PS declined from 12.8 to 5.4 ( P = 0.001). Low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol levels declined over the 9-year period ( P = 0.005 and P = 0.006, respectively), and the ratio of statin users increased markedly from 24% to 54% ( P = 0.001). Univariate regression analysis identified a positive correlation between the PS and LDL-C (r = 0.281; P = 0.01), and a strong positive correlation was found between the PS and LDL-C after adjusting for various risk factors for atherosclerosis. Conclusion Carotid atherosclerosis in patients with ESKD has decreased over the past 9 years, which may be a consequence of improvements in dyslipidemia management.