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The prevalence of diabetes is increasing worldwide and is the highest in the Western Pacific region, which includes Japan. There is an urgent need for the development of new diabetic kidney disease (DKD) biomarkers, in addition to those currently available from early diagnosis and specific detection to prognostic prediction and assessment of treatment response. Multiple biomarkers for DKD have been described and validated. There are some biomarkers which are available in clinical setting and novel. Traditional biomarkers include albumin, which has been well used for a long time and important for diagnosis of early DKD, neutrophil gelatinase-associated lipocalin, α-1-microglobulin, kidney injury molecule-1, L-type fatty acid binding protein, angiotensinogen, cystatin C, N-acetyl-glucosaminidase, and so on. A variety of factors have been shown to contribute to the progression of DKD. As chronic inflammation is one of these factors, all inflammatory cytokines can be used as biomarkers of DKD. Serum interleukin (IL)-6, IL-8, IL-18, monocyte chemoattractant protein, and interferon-inducible protein are reportedly higher in the urine of patients with early kidney damage. Serum and urinary tumor necrosis factor-α is also reportedly elevated from the early stage of DKD. In addition, some growth factor, such as transforming growth factor-β and connective tissue growth factor, and adhesion molecules are associated with end-stage kidney failure or mortality. Other factors include fetuin-A, which is a vascular calcification inhibitor that is secreted by the liver CD40 ligands, which are expressed in B cells, antigen-presenting cells, and vascular endothelial cells, and human α1 acid glycoprotein (orosomucoid).

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.

Background: Although 2018 revised ISN/RPS classification was proposed recently, until now, no reports have been made comparing the association of renal prognosis between 2018 revised ISN/RPS classification and 2003 ISN/RPS classification. The present study aimed to assess the usefulness, especially of activity and chronicity assessment, of the 2018 revised International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification for lupus nephritis (LN) in terms of renal prognosis compared to the classification in 2003.Methods: We retrospectively collected medical records of 170 LN patients from the database of renal biopsy in Fujita Health University from January 2003 to April 2019. Each renal biopsy specimen was reevaluated according to both the 2003 ISN/RPS classification and the 2018 revised ISN/RPS classification. Renal endpoint was defined as 30% decline of estimated glomerular filtration rate (eGFR). Results: A total 129 patients were class III/IV±V (class III, 44 patients; class IV, 35 patients; class III/IV+V, 50 patients). Mean age was 42 years, 88% were female, and median observation period was 50.5 months. Renal prognosis was significantly different among the classes, and significantly poor in the patients with higher modified National Institute of Health (mNIH) Chronicity index (C index, ≥4) by a log-rank test (p=0.05, p=0.02 respectively). By Cox proportional hazard models, only C index was significantly associated with renal outcome (Hazard Ratio; 1.32, 95% CI; 1.11-1.56, p≤0.01), while the classes, the 2003 activity and chronicity subdivision, and mNIH activity index had no significant association with renal outcome. Each component of C index was significantly associated with renal outcome in different models. Conclusion: This study demonstrates that the 2018 revised ISN/RPS classification was more useful in terms of association with renal prognosis compared to the 2003 ISN/RPS classification

Artificial intelligence is increasingly being adopted in medical fields to predict various outcomes. In particular, chronic kidney disease (CKD) is problematic because it often progresses to end-stage kidney disease. However, the trajectories of kidney function depend on individual patients. In this study, we propose a machine learning-based model to predict the rapid decline in kidney function among CKD patients by using a big hospital database constructed from the information of 118,584 patients derived from the electronic medical records system. The database included the estimated glomerular filtration rate (eGFR) of each patient, recorded at least twice over a period of 90 days. The data of 19,894 patients (16.8%) were observed to satisfy the CKD criteria. We characterized the rapid decline of kidney function by a decline of 30% or more in the eGFR within a period of two years and classified the available patients into two groups-those exhibiting rapid eGFR decline and those exhibiting non-rapid eGFR decline. Following this, we constructed predictive models based on two machine learning algorithms. Longitudinal laboratory data including urine protein, blood pressure, and hemoglobin were used as covariates. We used longitudinal statistics with a baseline corresponding to 90-, 180-, and 360-day windows prior to the baseline point. The longitudinal statistics included the exponentially smoothed average (ESA), where the weight was defined to be 0.9*(t/b), where t denotes the number of days prior to the baseline point and b denotes the decay parameter. In this study, b was taken to be 7 (7-day ESA). We used logistic regression (LR) and random forest (RF) algorithms based on Python code with scikit-learn library (https://scikit-learn.org/) for model creation. The areas under the curve for LR and RF were 0.71 and 0.73, respectively. The 7-day ESA of urine protein ranked within the first two places in terms of importance according to both models. Further, other features related to urine protein were likely to rank higher than the rest. The LR and RF models revealed that the degree of urine protein, especially if it exhibited an increasing tendency, served as a prominent risk factor associated with rapid eGFR decline.

With the global problem of aging, it has become more difficult to improve the prognosis of older dialysis patients. Extended-hours hemodialysis offers longer treatment time compared to conventional hemodialysis regimen and provides favorable metabolic status, hemodynamic stability, and increased dietary intake. Despite prior studies reporting that in-center extended-hours hemodialysis can reduce the mortality rate, the treatment impact on elderly patients remains unclear. Therefore, we examined the association between extended-hours hemodialysis compared to conventional hemodialysis and all-cause mortality. Survival analyses using Cox proportional hazard model with multivariable adjustments and propensity-score based method were performed to compare mortality risk between 198 consecutive patients who started in-center extended-hours hemodialysis (Extended-HD) and 1407 consecutive patients who initiated conventional hemodialysis. The median age was 67.1 years in the Extended-HD group and 70.7 years in the conventional hemodialysis group. Extended-HD was associated with lower all-cause mortality in overall patients and the subgroup >70 years (adjusted hazard ratios of 0.60 [95% CI, 0.39-0.91] and 0.35 [95% CI, 0.18-0.69], respectively). There was a significant interaction between age >70 years and Extended-HD. In conclusion, extended-hours hemodialysis was associated with a lower mortality rate, especially in elderly patients.

In recent years, cell-free concentrated ascites reinfusion therapy has been used to treat patients with malignant ascites. However, concentrated ascites reinfusion therapy involves enrichment and reinfusion of useful proteins and inflammatory cytokines. Therefore, fever is a primary side effect and significant problem for patients with ascites. We removed IL-6, an inflammatory cytokine, by mixing malignant ascites and the hexadecyl group adsorbent from a β2 -microglobulin-adsorbing column (Lixelle S-15). As a result, the hexadecyl group adsorbent did not adsorb the albumin of malignant ascites but adsorbed 43% of IL-6. To investigate the effect of the hexadecyl group adsorbent on hepatocytes, the adsorbed ascites was added to a human hepatoma cell line (HepG2), and the gene expression levels of albumin and serum amyloid A protein were examined. After absorption, ascites showed significantly suppressed serum amyloid A protein expression and significantly increased albumin gene expression compared to before adsorption. Our results suggest that incorporation of Lixelle to filter and concentrate malignant ascites can suppress inflammatory responses and reduce the inhibition of albumin synthesis in the liver after reinfusion.

Background and Aims Aortic stenosis (AS) in Japanese hemodialysis (HD) patients is sometimes pointed out by periodic transthoracic echocardiography. In general population, heart failure symptoms become severer with progress of AS. In HD patients, there is a possibility that AS cause blood pressure decline and congestive heart failure which are one of the reasons for censoring HD. There were no large-scale prospective observational studies relating to cardiovascular (CV) events and mortality in HD patients with AS, therefore we investigated whether AS was associated with incidence of CV events and mortality in HD patients. Method This study was a prospective cohort analysis which 4 facilities in Japan participated. The subjects who were over 20 years and underwent maintenance HD for at least 12 months were enrolled at timing of receiving transthoracic echocardiography. Patients were classified into following 2 group (AS group: mean pressure gradient (PG) ≥ 20 mmHg or aortic valve area (AVA) ≤ 1.0 cm2 or maximum blood velocity (Vmax) ≥ 2.0 m/s, no AS group: others). Four hundred sixty-four patients were followed up for 2 years. The primary outcome was defined as all-cause mortality. The secondary outcomes were incidences of CV events, stroke and hospitalization due to peripheral artery disease (PAD). Baseline was set at the time of transthoracic echocardiography examination. We compared the mortality and incidences of events between the 2 groups by a multivariate Cox proportional hazard model. In addition, we extracted risk factors relevant to AS by a multivariate logistic regression model. Results There were 79 patients (17.0 %) in the AS group among 464 patients. Older age and longer dialysis vintage were significantly associated with comorbidity of AS (multivariate-adjusted odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03-1.10; p < 0.001, OR, 1.05; 95% CI, 1.01-1.08; p = 0.01, respectively). Meanwhile, gender, diabetes mellitus and serum phosphate were not associated with comorbidity of AS. During follow up period (median, 2.3 years), 31 patients (6.7 %) died. There was no significant difference in all-cause mortality between the 2 groups (multivariate-adjusted hazard ratio [HR] for no AS group, 0.68; 95% CI, 0.24 – 1.91; p = 0.46). Furthermore, there were no significant associations between comorbidity of AS and the 3 secondary outcomes (HR, 0.25; 95% CI, 0.03 – 2.00; HR, 1.33; 95% CI, 0.34 – 5.21; HR, 1.50; 95%CI, 0.36 – 6.29, respectively). There were also no significant associations between comorbidity of severe AS defined as Vmax ≥ 2.0 m/s to ≥ 3.0 m/s and all the outcomes including all-cause mortality. On the other hand, tumor bearing was a risk factor for all-cause mortality (HR, 1.65; 95% CI, 1.04 - 2.61), and hypoalbuminemia was a risk factor for mortality from infection (HR, 0.13; 95% CI, 0.02-0.90). Conclusion This research showed that there were also no significant associations between comorbidity of AS and outcomes such as all-cause mortality, incidence of CV events, stroke, and PAD during the follow-up period of 2 years. The death caused by infection and malignant tumor accounted for more than 50 % of total all-cause death. It indicates that physical condition and tumor-bearing affect the mortality stronger than AS in a short term. We continue annual follow up and evaluate the impact of AS itself and vascular calcification causing AS after a long term like 5 years.

Background:Several reports indicate that extracellular volume predicted by bioimpedance analysis method is associated with hydration status of hemodialysis patients.Theory:Fundamentally, uric acid does not cross cell membranes by simple diffusion, either by facilitated diffusion or by active transport. In addition, uric acid cannot move through cell membranes in most tissues other than those involved in uric acid excretion. These facts support the interpretation that uric acid distribution volume would therefore correlate with extracellular volume.Methods:We examined correlation between uric acid distribution volume calculated by uric acid mass-balance modeling from regular blood test results and extracellular volume predicted by bioimpedance analysis predicted by BCM (Fresenius Medical Care) in 53 patients.Results:There was a significant correlation between uric acid distribution volume ( x) and extracellular volume predicted by bioimpedance analysis ( y): y = 0.69 x + 3.39, r2 = 0.61, p Conclusion:Uric acid distribution volume calculated by uric acid mass-balance modeling from regular blood test results may be an alternative marker of extracellular volume predicted by bioimpedance analysis.

This study aimed to clarify the relationship between serum high-density lipoprotein cholesterol (HDL-C) level and incidence of CV events. Moreover, the relationship stratified by gender was evaluated. The study database was derived from a multicenter, prospective, cohort study that included 1520 incident dialysis patients in Aichi Prefecture, Japan. Baseline was defined as the time of dialysis initiation and outcome as incidence of CV event. The enrolled patients were first classified into four quartile groups (Q1, Q2, Q3, and Q4; Q1 was the lowest serum HDL-C) based on serum HDL-C level. A multivariate Cox proportional hazards analysis was conducted using the stepwise regression method to determine factors associated with outcomes and was performed in each gender. The log-rank test revealed significant differences in the incidence of CV events between not only the four groups (p = 0.003) but also the male and female patients (HR, 0.74; 95% CI, 0.59–0.92; p

Supplemental material, Shinzato_T_Suppl_mat_v04 for Uric acid distribution volume calculated by kinetic modeling and extracellular volume predicted by bioimpedance method by Toru Shinzato, Shigeru Nakai, Takahito Ito, Kazuhiko Shibata, Teppei Matsuoka, Shinya Kato, Takeshi Aoki, Ikuto Masakane, Hiroki Hayashi, Naotake Tsuboi, Midori Hasegawa, Daijo Inaguma, Yukio Yuzawa and Susumu Ookawara in The International Journal of Artificial Organs

Additional file 1: Supplementary data 1. Description of the cohort used in the present study. Figure S1. Frequency and proportion of pathological diagnoses. Supplementary data 2. Diagnosis rate of IgG4-related TIN (2003-2008 and 2009-2015). Table S1. Baseline characteristics of the present patients by diagnosis or non-diagnosis of IgG4-related TIN at the initial examination.

The rate of hepatitis B infection among hemodialysis patients is high. However, it is not clear if this rate reflects the infection rate among patients with chronic kidney disease (CKD). Therefore, we evaluated the rate of hepatitis B infection among patients with CKD. This is an important clinical issue when considering the risk of infection to medical staff when performing invasive procedures in this clinical population. A retrospective, observational study was conducted among stable, non-dialysis patients with CKD who attended a CKD educational program at our hospital, between August 2012 and October 2017. We collected patients' background and markers of hepatitis infection (HBsAg, HBcAb and HBsAb, as well as HBV-DNA when available) from medical records. The data from 496 patients (373 men and 123 women, with a mean age of 69.3 ± 13.0 years and mean level of creatinine of 3.15 ± 1.72 mg/dL, AST of 21.6 ± 10.5 IU/L, and ALT of 17.3 ± 12.5 IU/L), were included in the analysis. The rate of positive testing for hepatitis B virus infection was as follows: HBsAg, 1.6%; HBsAb, 16.5%; and HBcAb, 21.4%. Of the patients with a negative HBsAg test, 20.1% tested positive for HBcAb. Of the 66 patients in whom HBV-DNA testing was performed, 10.6% tested positive. The rate of hepatitis B virus infection was specifically higher among patients ≥71-years-old. In patients with CKD, the rate of HBsAg positivity is high. Rate of HBcAb positivity is higher particularly in older individuals.

Aim Some observational studies of the general population showed that resting heart rate was associated with mortality. However, the relationship was unclear in dialysis patients. Methods The study was a multicenter prospective cohort analysis including 1,102 patients. Patients were classified into four groups based on resting heart rate just before starting the first dialysis session

Background: Several human studies reported that the combined use of renin-angiotensin system blockers (RASBs) and vitamin D receptor activators (VDRAs) resulted in decreased urinary protein excretion. However, it is unknown whether this combination therapy influences the incidence of cardiovascular (CV) events in dialysis patients. Methods: The study was a multicenter nonrandomized prospective cohort analysis including 1,518 patients. Patients were classified into 4 groups based on medications prescribed before dialysis initiation: those who did not receive RASBs or oral VDRAs (N group), those receiving only RASBs, those receiving only VDRAs, and those receiving a combination of RASBs and VDRAs (RD group). CV events after dialysis initiation were compared using the log-rank test. Factors contributing to the incidence of CV events were examined using multivariate Cox proportional hazard regression analysis. Results: Significant differences were observed in the incidence of CV events and all-cause mortality between the 4 groups (p = 0.021 and p = 0.001, respectively). Cox proportional hazard analysis revealed that the incidence of CV events was significantly lower in the RD group than in the N group (hazard ratio [HR] = 0.65, 95% confidence interval [CI]: 0.50-0.86, p = 0.002). Multivariate analysis revealed that the incidence of CV events was significantly lower in the RD group than in the N group (HR = 0.66, 95% CI: 0.47-0.93, p = 0.016). Conclusion: Combination therapy with RASBs and VDRAs in patients before dialysis initiation was associated with a reduction in CV events during maintenance dialysis.

Background/Aim: High serum alkaline phosphatase (ALP) levels predict mortality independent of bone metabolism parameters and liver function test results in patients on hemodialysis. The relationship between serum ALP at dialysis initiation and mortality during maintenance dialysis is unknown; therefore, we aimed to identify an association. Methods: This multicenter, prospective cohort study analyzed 1,213 patients registered in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis from October 2011 to September 2013. Patients were divided into 2 groups based on serum ALP levels. All-cause mortality and incidences of cardiovascular events after dialysis initiation were compared using the log-rank test and multivariate Cox proportional hazard regression analysis. We performed stratified analysis based on parathyroid hormone (PTH) levels. Results: During the follow-up, 109 (18.0%) and 86 (14.1%) patients died in the high ALP group (232 ≥IU/L; High ALP group) and low ALP group (232 p = 0.014). The serum ALP level was significantly correlated with the all-cause mortality rate (hazard ratio = 1.17 per 100 IU/L increase of ALP, 95% confidence interval: 1.11–1.24, p < 0.001). The all-cause mortality rate was significantly higher in the High ALP group among patients with low (p = 0.012 and p = 0.005, respectively) than in the Low ALP group; there was no significant difference among patients with a high (≥300 pg/mL) PTH level (p = 1.000). Conclusion: The serum ALP level at dialysis initiation is associated with all-cause mortality during maintenance dialysis.

Patients with malignancy have a poorer prognosis than others do, which must be taken into consideration when treating them for chronic kidney disease (CKD). However, there are few studies investigating their prognosis. This was an observational study of 515 (394 men and 121 women) stable non-dialysis patients with CKD who attended a CKD educational program. Mean age was 68.8 ± 13.0 years. Median follow-up was 968.5 days. Mean creatinine was 3.4 ± 1.6 mg/dL. Of these, 63 had malignancy and 452 did not; 20.6% of the former and 11.9% of the latter group died by the end of the study period (P = 0.0548). Malignancy was not associated with all-cause mortality (HR: 1.3475, 95% CI: 0.7202-2.5214, P = 0.3507) but with malignancy-associated mortality (HR: 3.9477, 95% CI: 1.6348-9.5331, P = 0.0023). Renal replacement therapy was not associated with mortality. Since malignancy greatly affects the prognosis, it must be taken into consideration when treating these patients.

Some studies have shown that the estimated glomerular filtration rate (eGFR) at the time of initiating dialysis was associated with mortality. However, the relationship between ratio of blood urea nitrogen to serum creatinine (BUN/Cr) and mortality is unknown. The study was a multicenter, prospective cohort analysis including 1520 patients. Patients were classified into four quartiles based on the BUN/Cr ratio at the dialysis initiation, with Q1 having the lowest ratio and Q4 the highest. All-cause mortality after initiating dialysis was compared using the log-rank test. All-cause mortality of Q1, Q2, and Q3 was compared with that of Q4 using multivariate Cox proportional hazard regression analysis. Moreover, we compared the renal parameters including BUN/Cr ratio, eGFR, and creatinine clearance for sensitivity and specificity using receiver operative characteristic (ROC) curve. Significant differences were observed in all-cause mortality among the four groups (p

Background Patients with chronic kidney disease (CKD) often have the complication of anaemia. Usage of an erythropoietin-stimulating agent accelerates iron deficiency because it promotes iron utilization. Recently, iron administration was reported to be effective for patients with cardiac failure. We examined the association between ferrokinetics and cardiac function in patients with CKD.Methods In this cross-sectional study, we examined 558 patients (424 men and 134 women; mean age, 68.9 ± 13.1 years) with CKD who were admitted to our hospital. We assessed cardiac function by ultrasonography and ferrokinetics through transferrin saturation (TSAT) and ferritin levels.Results The primary diseases of CKD were nephrosclerosis (n = 247), diabetic nephropathy (n = 154), chronic glomerulonephritis (n = 73), and others. The mean estimated glomerular filtration rate was 16.9 ± 9.3 mL/min/1.7 m2, and the haemoglobin (Hb) level was 11.0 ± 1.7 g/dL. The median of TSAT was 28.05%, and patients were divided in...

Patients with malignancy are reported to have poorer prognosis than those without malignancy. When patients with malignancy develop end-stage kidney disease, clinicians must determine treatment with consideration of prognosis. Furthermore, malignancy is sometimes found at time of dialysis initiation. However, prognosis of patients with malignancy at time of dialysis initiation has not been investigated. A total of 1524 patients with chronic kidney disease who initiated dialysis at 17 centers participating in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis were included. Patients initiated dialysis between October 2011 and September 2013. Mortality rates were compared between patients with and without malignancy. Types of malignancy and respective prognoses also were assessed. The study included 1030 men and 492 women with a mean age of 67.5 ± 13.1 years. Of these, 92 had malignancy and 1430 did not; 45.7% of the former group and 16.0% of the latter group died by March 2015 (P

Objective The National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (KDOQI) guidelines have recommended the use of arteriovenous fistula (AVF) at the initiation of dialysis. However, there are significant differences in the dialysis environments of Japan and the United States, and there are few people who receive hemodialysis via a central venous catheter (CVC) in Japan. The aim of the present study was to examine the association between the type of vascular access at the initiation of dialysis and the incidence of mortality in Japan. Methods This study was a prospective, multicenter, cohort study. The data was collected by the Aichi Cohort study of Prognosis in Patients newly initiated into dialysis (AICOPP) in which 18 Japanese tertiary care centers participated. The present study enrolled 1,524 patients who were newly introduced to dialysis (the patients started maintenance dialysis between October 2011 and September 2013). After excluding 183 patients with missing data, 1,341 patients were enrolled. The Cox proportional hazards model was used to evaluate mortality based on the type of vascular access. The types of vascular access were divided into four categories: AVF, arteriovenous graft (AVG), CVC changed to AVF during the course (CAVF), CVC changed to AVG during the course (CAVG). Results A multivariate analysis revealed that AVG, CAVF and CAVG were associated with a higher risk of mortality in comparison to AVF [hazard ratio (HR), 1.60; p=0.048; HR, 2.26; p= 0.003; and HR, 2.45; p=0.001, respectively]. Conclusion The research proved that the survival rate among patients in whom hemodialysis was initiated with AVF was significantly higher than that in patients in whom hemodialysis was initiated with AVG or CVC.

Two elderly patients (a 76-year-old man and a 75-year-old woman), who had been previously diagnosed with familial hypercholesterolemia (at 58 and 48 years of age, respectively) underwent long-term treatment with oral therapy and low-density lipoprotein (LDL) apheresis. As their LDL cholesterol levels remained high (>150 mg/dL and >120 mg/dL, respectively) and their familial hypercholesterolemia was complicated with angina pectoris, we added evolocumab to their prescription. Thereafter, their LDL cholesterol levels decreased rapidly, and the patients were successfully weaned from LDL apheresis. Evolocumab therapy should thus be considered when LDL apheresis cannot achieve the target LDL cholesterol levels, though the prognosis of such treatment remains unclear.

Background Usage of vitamin D receptor activator (VDRA) for chronic kidney disease (CKD) including patients on dialysis patients has been controversial yet. It is unknown when to begin or discontinue VDRA therapy, the type of VDRA to administer, and the method of delivery, intravenous or oral for survival in CKD patients. Therefore, we examined whether intravenous or oral VDRA early after dialysis initiation affected mortality in incident dialysis patients. Methods The study database was derived from the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP), a multicenter, prospective, cohort analysis of 1,520 consecutive patients who began dialysis at the 17 AICOPP group centers between October 2011 and September 2013. We excluded the 262 patients who died by March 2015, 15 patients were lost to follow-up, 241 patients with unconfirmed information about use of VDRA in March 2015, and 35 patients who discontinued VDRA between dialysis initiation and March 2015. Finally, 967 patients participated in the present study. We classified the participating patients into three groups according to the usage of VDRA in March 2015: no use of VDRA (NV group), oral VDRA (OV group), and intravenous VDRA (IV group) and compared their all-cause mortality. Results There were 104 deaths during the follow-up period (NV group, 27 cases; OV group, 53 cases; IV group, 24 cases). Significant differences between the cumulative survival rates were observed for the three groups (p = 0.010). The IV group was associated with low all-cause mortality compared to the NV group (Hazard ratio = 0.46, 95% CI = 0.24−0.89, p = 0.020) by multivariate Cox proportional hazard analysis using the stepwise method. Conclusions Our study shows that early introduction of intravenous VDRA to patients on hemodialysis seems to be associated with better prognosis.Trial Registration The trial registration no. is UMIN 000007096, registered on January 18, 2012. 298words, Text: 2967 words

Aim Some reports claim that intravenous iron supplements reduce serum phosphate levels in patients with chronic kidney disease (CKD), including those on dialysis. However, whether divalent oral iron supplements influence serum phosphate levels in patients with CKD remains unclear; thus, this study aimed to address this topic. Materials and methods The study database was derived from the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP), which is a multicenter, prospective, cohort study. Patients were classified into two groups: those who received iron orally (iron group, n = 255) from pre-dialysis to dialysis initiation and those who did not receive iron supplements (no-iron group, n = 1,261). Moreover, patients were classified into two groups (255 patients in each) by propensity score (PS) matching. We compared serum phosphate level at dialysis initiation and all-cause mortality. Multivariate regression analysis was used to extract factors contributing to serum phosphate level at dialysis initiation through a stepwise method. Results Serum phosphate levels at dialysis initiation were significantly lower in the iron group (all cohort, 6.0 ± 1.6 vs. 6.4 ± 1.9 mg/dL, p = 0.001; PS-matched cohort, 6.0 ± 1.6 vs. 6.5 ± 1.7 mg/dL, p = 0.001). Multivariate regression analysis revealed that oral iron supplementation was significantly correlated to serum phosphate level (p = 0.023). There were no significant differences in all-cause mortality after dialysis initiation. Conclusion This study showed that oral ferrous citrate or ferrous sulfate use during predialysis was associated with differences in serum phosphate level at dialysis initiation.

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.

In dialysis patients, physical function is associated with mortality. However, the association between physical function at the time of dialysis initiation and subsequent mortality remains unknown. A total of 1496 patients with chronic kidney disease who initiated dialysis at 17 centers participating in the Aichi Cohort Study of the Prognosis in Patients Newly Initiated into Dialysis, a multicenter prospective cohort study, were included. The patients were divided into the high (H)-, middle (M)-, and low (L)-score groups according to Barthel index (BI) at the time of dialysis initiation, and the all-cause, cardiovascular disease (CVD)-related, and infection-related mortality rates were compared. Moreover, factors affecting all-cause mortality were investigated. The effects of BI on mortality were assessed in the patients stratified by age, sex, and history of CVD or cerebral infarction. A log-rank test for the Kaplan–Meier survival curve showed significant differences between the three groups in all-cause, CVD-related, and infection-related mortality rates (p

The timing for initiating dialysis in chronic kidney disease is often determined by the clinical symptoms and estimated glomerular filtration rate (eGFR). However, very few studies have examined how the speed of kidney function decline before initiating dialysis relates to mortality after dialysis initiation. Here, we report our examination of the relationship between the speed of eGFR decline in the 3 months prior to dialysis initiation and mortality. The study included 1292 new dialysis patients who were registered in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis. The subjects were placed in 4 groups based on the speed of eGFR decline in the 3 months before initiating dialysis (eGFR at 3 months before initiation—eGFR at initiation)

Over 300,000 patients receive maintenance dialysis in Japan; managing these patients is extremely important. This study aimed to report on prior management of chronic kidney diseases and prognostication after dialysis initiation. Seventeen institutions participated in the Aichi cohort study of prognosis in patients newly initiated into dialysis and recruited patients over a period of 2 years. Exclusion criteria were (1) patients under 20 years; (2) patients who died before hospital discharge; and (3) patients who could not provide consent. Here, we showed data on dialysis initiation time. Of 1524 patients with mean age of 67.5 ± 13.0 years, 659 patients were put on dialysis following diabetic nephropathy diagnosis. At dialysis initiation time, creatinine and estimated glomerular filtration rate levels were 8.97 ± 3.21 mg/dl and 5.45 ± 2.22 ml/min/1.73 m2, respectively. Medications taken were angiotensin II receptor blockers in 866; angiotensin-converting enzyme inhibitors in 135; calcium antagonist in 1202; and diuretics, alone or in combination, in 1059. Among patients with diabetic nephropathy, many had increased body weight and systolic blood pressure and were taking loop and thiazide diuretics at dialysis initiation time. Many patients with diabetic nephropathy had coronary artery disease and percutaneous coronary intervention. Many patients with diabetic nephropathy who registered for this study had coronary artery disease and problems with excess body fluid. Further analyses may clarify how underlying conditions and disease management before and after dialysis initiation affect prognosis.

Background: Recently, sleep apnea syndrome (SAS) has been associated with hypertension, cardiovascular disease and death. Patients with chronic kidney disease (CKD) have higher rates of SAS, atherosclerotic complications and death than do patients without CKD. Although the relationship between SAS and atherosclerosis is well known, few papers have described this relationship in humans, especially in CKD patients. Patients and Methods: This was a cross-sectional study of 110 clinically stable, non-dialysis patients with CKD who attended a CKD educational program from April 2014 to September 2015. The diagnosis of SAS and its severity were assessed using a type 3 portable monitor. Other atherosclerosis-related data were obtained from the patients' medical records in order to determine the factors associated with the severity of SAS. Results: 95 men and 15 women with a mean age of 71.4 ± 9.9 years were included in the study. The patients' mean body mass index was 24.0 ± 3.9, their mean blood pressure 134.3 ± 21.2/73.6 ± 13.4 mm Hg and their mean estimated glomerular filtration rate 19.8 ± 9.5 ml/min/1.7 m2. Adjusted plaque score was a significant predictor of severe SAS (odds ratio = 1.13, p = 0.0182). Mixed plaque was significantly associated with severe SAS (correlation ratio = 0.48, p < 0.0001). Conclusions: Many patients with CKD also have SAS. Our findings demonstrate the relationship between plaque score and the severity of SAS.

ObjectivesPatients with peripheral artery disease (PAD) are reported to have a poorer prognosis than those without PAD. PAD is sometimes found at dialysis initiation, but its influence on the prognosis in these patients has not been investigated. We aimed to compare the mortality rate between patients with PAD at the time of dialysis initiation and those without PAD.DesignWe undertook an observational prospective multicenter study of patients starting dialysis treatment. Data were collected on patients’ sex, age, presence of PAD, medication, medical history and clinical and laboratory data.SettingSeventeen centers participated in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis.ParticipantsA total of 1524 patients with chronic kidney disease started dialysis from October 2011 to September 2013. The patients were followed-up until March 2015. During this time, there were two patients who lost the follow-up.Primary and secondary outcome measuresThe primary outcome was defined as all-cause mortality. The secondary outcomes were defined as each cause of mortality.ResultsThis study included 1030 men and 492 women with a mean age of 67.50±13.10 years. Of these, 71 had PAD and 1451 did not have PAD. After a median follow-up of 814.5 days, 33.80% of the former group and 17.00% of the latter group had died in March 2015 (p=0.001). After adjusting for confounding factors, PAD at dialysis initiation remained an independent risk factor for mortality (pConclusionsPatients with PAD at the time of dialysis initiation had a poorer prognosis than patients without PAD. Therefore, the presence of PAD in patients starting dialysis should be considered for their monitoring and follow-up.

Background: Few studies have focused on the association between history of ischemic stroke at predialysis stage and mortality after dialysis initiation. Objective: To examine whether history of stroke in incident dialysis patients is associated with mortality, including all-cause and cardiovascular (CV)-related mortality. Methods: The study database was derived from the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis, a multicenter, prospective, cohort analysis. We classified patients into 2 groups according to their history of ischemic stroke and compared their outcomes. Propensity scores (PSs) represented the probability of being assigned to a group with or without a history of ischemic stroke. We defined the following outcomes: all-cause mortality; CV-related mortality; non-CV-related mortality; infection-related mortality; and stroke event after dialysis initiation. Factors contributing to the outcomes were examined using stepwise multivariate Cox proportional hazards analysis. Results: All-cause mortality was significantly higher in the ischemic stroke group (log-rank test p < 0.001). All-cause, non-CV-related, and infection-related mortality and stroke event after dialysis initiation were significantly higher in the ischemic stroke group after PS matching (log-rank test: p < 0.001, Conclusion: The present study revealed that history of ischemic stroke before dialysis initiation was associated with all-cause, non-CV-related, and infection-related mortality and stroke event after dialysis initiation during maintenance dialysis.

Hypertension is common in patients with chronic kidney disease. Whether blood pressure management before dialysis initiation influences prognosis during maintenance dialysis remains unclear. Hence, we surveyed the status of antihypertensive drug use in incident dialysis patients. Moreover, we examined the association between antihypertensive drug use patterns at the time of dialysis initiation and mortality. We used a database derived from the multicenter prospective Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis, which included 1520 incident dialysis patients in Aichi prefecture, Japan. The baseline in the present study was set as the time of dialysis initiation. We examined antihypertensive drug prescription patterns at baseline, as well as the association between use of antihypertensive drugs and mortality after dialysis initiation. Among all participants, 1440 were taking at least one antihypertensive drug. The rate of calcium channel blocker (CCB) use was highest, accounting for 74.3%. CCB use was significantly associated with lower all-cause and cardiovascular-related mortality (hazard ratio [HR]: 0.62 and 0.57, 95% confidence interval [CI]: 0.46-0.85 and [0.35-0.91], respectively). Compared with no use of either drug, combination therapy with a renin angiotensin system blocker (RASB) and CCB was significantly associated with lower mortality (HR: 0.51, 95% CI: 0.34-0.76). The present study demonstrated that antihypertensive drugs were used in 95% of incident dialysis patients. In addition, use of a CCB and combination therapy with a CCB and RASB at the time of dialysis initiation was associated with lower mortality during maintenance dialysis.

Background Patients with late referral and positive history of volume overload may have a poor prognosis after initiating dialysis due to insufficient and/or inadequate management of complications of renal failure and the lack of better dialysis preparation. Little is known about the influence of the relationship between history of volume overload and late referral on prognosis. Methods We analyzed 1475 patients who had initiated dialysis for the first time from October 2011 to September 2013. late referral was defined as referral to a nephrologist

Whether vitamin D receptor activator (VDRA) use is beneficial in chronic kidney disease (CKD) is unclear, because it is possible that VDRA increases serum fibroblast growth factor 23 (FGF23) levels. We will conduct a randomized controlled trial in predialysis patients to determine the effect of VDRA alone or in combination with lanthanum carbonate (LC) on serum FGF23 levels. This is a single-center, open-label, randomized controlled trial. Enrollment will commence February 1, 2018, using the following inclusion criteria: (1) age ≥ 20 years, (2) CKD with an estimated glomerular filtration rate of 10–45 mL/min/1.73 m2, (3) serum adjusted calcium level

An increasing number of patients worldwide require dialysis as a result of hypertensive nephrosclerosis (HTN). However, in Japan, mortality in patients with end-stage renal disease (ESRD) has not been well by primary kidney disease including HTN and diabetic nephropathy (DN). Hence, we examined the differences in mortality among the primary kidney diseases of incident dialysis patients. The study was a multicenter prospective cohort analysis including 1520 incident dialysis patients in Aichi prefecture, Japan. We classified patients into three groups according to the primary kidney disease [i.e., a HTN group, n = 384, a DN group n = 658, and a chronic glomerulonephritis (CGN) group, n = 224]. In addition, we classified patients into the HTN group and the DN group using propensity score matching. We compared outcomes including all-cause and infection-related mortality. The mortality rates of the HTN, the DN, and the CGN group, were 135.9, 64.2, and 34.8 per 1000 patient years, respectively. All-cause mortality and infection-related mortality rates in the HTN group were as high as those in the DN group after adjustment for age, gender, history of cardiovascular disease, and estimated glomerular filtration rate. No significant difference of all-cause mortality was observed after propensity score matching between the two groups (Logrank test: p = 0.523). The present study was Japan’s first large-scale prospective cohort to demonstrate that HTN is the second most common cause of ESRD. In addition, the prognosis of patients with HTN was as poor as that of patients with DN.

Table S1. Background characteristics of patients who underwent or did not undergo echocardiography. (DOCX 35 kb)

Figure S1. Cumulative incidence functions for CVD-related death for four groups stratified according to late nephrologist referral and history of volume overload. (PDF 21 kb)

Yuzo Watanabe, Hideki Hirakata, Kazuyoshi Okada, Hiroyasu Yamamoto, Kazuhiko Tsuruya, Ken Sakai, Noriko Mori, Noritomo Itami, Daijo Inaguma, Kunitoshi Iseki, Akiko Uchida, Yoshindo Kawaguchi, Seiji Ohira, Masashi Tomo, Ikuto Masakane, Tadao Akizawa, and Jun Minakuchi, for the Japanese Society for Hemodialysis Therapy Guideline Commission of Maintenance Hemodialysis Investigation Subgroup Commission on Withholding and Withdrawal from Dialysis

Yuzo Watanabe, Kunihiro Yamagata, Shinichi Nishi, Hideki Hirakata, Norio Hanafusa, Chie Saito, Motoshi Hattori, Noritomo Itami, Yasuhiro Komatsu, Yoshindo Kawaguchi, Kazuhiko Tsuruya, Yoshiharu Tsubakihara, Kazuyuki Suzuki, Ken Sakai, Hideki Kawanishi, Daijo Inaguma, Hiroyasu Yamamoto, Yoshiaki Takemoto, Noriko Mori, Kazuyoshi Okada, Hiroshi Hataya, Takashi Akiba, Kunitoshi Iseki, Tadashi Tomo, Ikuto Masakane, Tadao Akizawa, and Jun Minakuchi, for “Hemodialysis Initiation for Maintenance Hemodialysis” Guideline Working Group, Japanese Society for Dialysis Therapy

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.

Background In patients with chronic kidney disease (CKD), prevalence of sleep apnoea syndrome (SAS) is reported to be markedly high. However, the factors associated with severity of SAS in such patients rarely have been reported. Methods This was a cross-sectional study of 100 stable non-dialysis patients with CKD who attended a CKD educational programme from April 2014 to August 2015. Diagnosis of SAS and its severity were assessed using a type-3 portable monitor. Results Eighty-six men and 14 women with a mean age of 71.6 ± 9.7 years were included. Mean apnoea-hypopnoea index (AHI) was 26.0 ± 13.8. Severe SAS was seen in 39 patients. Significant differences in brain natriuretic peptide (BNP) level (213.6 ± 329.6 pg/mL vs 107.8 ± 141.3 pg/mL, P 0.05) and cardiothoracic ratio (CTR, 52.4% ± 6.3% vs 49.6% ± 5.7%, P 0.05) were seen between patients with and without severe SAS. After adjusting for various parameters, BNP level, CTR, and diameter of the inferior vena cava at the end of inhalation were found to correlate with AHI. Conclusions In patients with CKD, prevalence of severe SAS is extremely high. In these patients, fluid retention, rather than systolic or diastolic function, correlates with severity of SAS.

Background Sepsis is a systemic inflammatory response syndrome caused by infectious disease. Severe sepsis and septic shock are extremely serious conditions with poor prognoses. It is reported that cytokines are deeply involved in the disease mechanism. Continuous hemodiafiltration (CHDF) using a poly(methyl methacrylate) (PMMA) membrane is reported to adsorb various cytokines and improve the status of patients with sepsis. Recently, another cytokine-adsorbing hemofilter, acrylonitrile-co-methallyl sulfonate surface-treated (AN69ST) membrane, has become available for CHDF in patients with sepsis. However, the clinical efficacy of this membrane remains unclear. Therefore, in this study, we compared the efficacy of AN69ST and PMMA membranes. Methods This retrospective study included patients with severe sepsis or septic shock who underwent CHDF for at least 24 h in the intensive care unit from January 2013 to August 2016. Results This study included 49 patients who underwent CHDF, 32 using an AN69ST membrane and 17 using a PMMA membrane. In the AN69ST and PMMA groups, average age was 71.1 ± 11.4 years and 74.7 ± 9.4 years, respectively, and percentage of men was 71.9 and 88.2%, respectively. Severity of sepsis and vital signs were not significantly different between groups at the start of CHDF. In addition, 28-day mortality was not significantly different between groups (43.8 vs. 35.3%, P = 0.1625). However, heart rate in the AN69ST group decreased significantly early in the course of CHDF (6, 12, and 24 h, P

In patients on maintenance dialysis, increased serum calcium levels are known to be associated with a poor prognosis. However, it is not known whether serum calcium levels at dialysis initiation have an impact on subsequent prognosis. The subjects were patients who were newly initiated dialysis at the 17 Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP) group centers. The study included 1524 patients who were at least 20 years old, had CKD, and provided written consent. We excluded one patient whose serum adjusted calcium was not assessed and six patients whose outcomes were unknown. Thus, we enrolled 1517 subjects into the study. The patients were divided into the following five groups: (1) G1 with a serum adjusted calcium level