Yukio Yuzawa

OBJECTIVE: Clinicopathological characteristics, renal prognosis, and mortality in patients with type 2 diabetes and reduced renal function without overt proteinuria are scarce. RESEARCH DESIGN AND METHODS: We retrospectively assessed 526 patients with type 2 diabetes and reduced renal function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), who underwent clinical renal biopsy and had follow-up data, from Japan's nationwide multicenter renal biopsy registry. For comparative analyses, we derived one-to-two cohorts of those without proteinuria versus those with proteinuria using propensity score-matching methods addressing the imbalances of age, sex, diabetes duration, and baseline eGFR. The primary end point was progression of chronic kidney disease (CKD) defined as new-onset end-stage renal disease, decrease of eGFR by ≥50%, or doubling of serum creatinine. The secondary end point was all-cause mortality. RESULTS: Eighty-two patients with nonproteinuria (urine albumin-to-creatinine ratio [UACR] <300 mg/g) had lower systolic blood pressure and less severe pathological lesions compared with 164 propensity score-matched patients with proteinuria (UACR ≥300 mg/g). After a median follow-up of 1.9 years (interquartile range 0.9-5.0 years) from the date of renal biopsy, the 5-year CKD progression-free survival was 86.6% (95% CI 72.5-93.8) for the nonproteinuric group and 30.3% (95% CI 22.4-38.6) for the proteinuric group (log-rank test P < 0.001). The lower renal risk was consistent across all subgroup analyses. The all-cause mortality was also lower in the nonproteinuric group (log-rank test P = 0.005). CONCLUSIONS: Patients with nonproteinuric diabetic kidney disease had better-controlled blood pressure and fewer typical morphological changes and were at lower risk of CKD progression and all-cause mortality.

BACKGROUND: An overweight person is at high risk for hypertensive renal damage. The effect of weight on the association between systolic blood pressure (SBP) and albuminuria remains unknown in patients with histologically diagnosed hypertensive nephrosclerosis. METHODS: A total of 97 patients with biopsy-confirmed hypertensive nephrosclerosis were recruited from 13 centers throughout Japan. We examined the relationship between SBP and proteinuria among those who were overweight, which is defined as a body mass index ≥25 kg/m2, and those who were not. We examined the interaction of weight and SBP with albuminuria at baseline and with the changes in estimated glomerular filtration rate (eGFR) during the observational period. RESULTS: Our results included mean age (54 years old), blood pressure (138/80), eGFR (53 ml/min/1.73 m2), and urine albumin levels (0.2 g/day). SBP was significantly correlated with log-transformed urine albumin levels (r = 0.4, P = 0.01) in patients who were overweight (n = 38) compared with patients who were not overweight (n = 59). Multiple regression analysis revealed that the interaction between being overweight and SBP with respect to albuminuria was significantly correlated with the log-transformed urine albumin level (β = 0.39, P = 0.047) and was independent of age, sex, and potential confounding factors. The interaction between weight and SBP ≥140 mm Hg was significantly associated with a greater decrease in eGFR in the following 3 years. CONCLUSIONS: Being overweight may enhance susceptibility to hypertensive glomerular damage and may eventually lead to renal progression in patients with hypertensive nephrosclerosis.

BACKGROUND: The prognostic value of the EUVAS-proposed histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis has been evaluated throughout the world. Here, we performed a Japanese nationwide biopsy survey to assess the association between this histopathological classification and renal prognosis after 2-year follow-up in ANCA-associated glomerulonephritis. METHODS: We collected 67 renal biopsy materials of the 321 entries in the RemIT-JAV-RPGN cohort study, and assessed their histologies. Based on the EUVAS-proposed histopathological classification and some histological parameters, we statistically evaluated renal survival and the comparison of renal function for 2 years. RESULTS: Based on the histopathological classification, the largest number of biopsy samples belonged to the Focal class, followed by the Mixed, Crescentic, and Sclerotic classes (n = 30, 19, 10, 8, respectively). Although the number of events might be too low (four patients with renal death) to make this conclusion, the Focal and Mixed classes had higher renal-survival rates compared to the others in the renal-survival curve. Comparing renal function among all classes, the estimated glomerular filtration rate (eGFR) throughout 2-year follow-up period was significantly higher in the Focal class compared to the other 3 classes. The eGFR-values in the Crescentic, Mixed, and Sclerotic classes increased with time. Based on both combined results, the Focal class could be the best prognosis. CONCLUSION: This histopathological classification was valuable for both the stratification of renal function and the estimation of partial renal survival during 2-year follow-up in ANCA-associated glomerulonephritis.

The accumulation of amyloid-β protein (Aβ) and tau in the brain is a major pathological change related to Alzheimer's disease. We have continued to develop Extracorporeal Blood Aβ Removal Systems (E-BARS) as a method for enhancing Aβ clearance from the brain. Our previous report revealed that dialyzers effectively remove blood Aβ and evoke large Aβ influxes into the blood, resulting in a decrease in brain Aβ accumulation after initiating hemodialysis, and that patients who underwent hemodialysis had lower brain Aβ accumulation than those who did not. Here, plasma total tau concentrations from 30 patients undergoing hemodialysis were measured using an ultrasensitive immunoassay and compared to those from 11 age-matched controls. Plasma total tau concentrations were higher in patients with renal failure regardless of whether they underwent hemodialysis, suggesting the involvement of the kidneys in tau degradation and excretion. Hemodialyzers effectively removed blood Aβ but not extracorporeal blood tau. The influx of tau into the blood was observed at around the 1 h period during hemodialysis sessions. However, the influx amount of tau was far smaller than that of Aβ. Furthermore, histopathological analysis revealed similar, not significantly less, cerebral cortex phosphorylated tau accumulation between the 17 patients who underwent hemodialysis and the 16 age-matched subjects who did not, although both groups showed sparse accumulation. These findings suggest that hemodialysis may induce both tau and Aβ migration into the blood. However, as a therapeutic strategy for Alzheimer's disease, it may only be effective for removing Aβ from the brain.

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, <0.001, 0.002, and 0.002, respectively). History of ischemic stroke was associated with all-cause mortality in univariate analysis (hazard ratio [HR] 1.85, 95% CI 1.44-2.37). History of ischemic stroke before dialysis initiation was associated with all-cause mortality in multivariate analysis (HR 1.39, 95% CI 1.05-1.85). 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.

Some variables including age, comorbidity of diabetes, and so on at dialysis initiation are associated with patient prognosis. Cardiovascular (CV) events are a major cause of death, and adequate models that predict prognosis in dialysis patients are warranted. Therefore, we created models using some variables at dialysis initiation. We used a database of 1,520 consecutive dialysis patients (median age, 70 years; 492 women [32.4%]) from a multicenter prospective cohort study. We established the primary endpoint as a composite of the incidence of first CV events or all-cause death. A multivariable Cox proportional hazard regression model was used to construct a model. We considered a complex and a simple model. We used area under the receiver operating characteristic curve (AUROC) to assess and compare the predictive performances of the prediction models and evaluated the improvement in discrimination using the complex model versus the simple model using net reclassification improvement (NRI). We then assessed integrated discrimination improvement (IDI) to evaluate improvements in average sensitivity and specificity. Of 392 deaths, 152 were CV-related. Totally, 506 CV events occurred during the follow-up period (median 1,285 days). Finally, 692 patients reached the primary endpoint. Baseline data were set at dialysis initiation. AUROC for the primary endpoint was 0.737 (95% confidence interval [CI], 0.712-0.761) in the simple model and 0.765 (95% CI, 0.741-0.788) in the complex model. There were significant intergroup differences in NRI (0.44; 95% CI, 0.34-0.53; p < 0.001) and IDI (0.02; 95% CI, 0.02-0.03; p < 0.001). We prepared a Shiny R application for each model to automatically calculate the predicted occurrence probability (https://statacademy.shinyapps.io/App_inaguma_20190717/). The complex model made more accurate predictions than the simple model. However, the intergroup difference was not significant. Hence, the simple model was more useful than the complex model. The tool was useful in a real-world clinical setting because it required only routinely available variables. Moreover, we emphasized that the tool could predict the incidence of CV events or all-cause mortality for individual patients. In the future, we must confirm its external validity in other prospective cohorts.

The glomerulus primarily comprises mesangial cells, glomerular microvascular endothelial cells, and podocytes. IgA nephropathy is the most common primary glomerulonephritis worldwide and has a risk of progression to end-stage renal disease. IgA nephropathy is characterized by predominant IgA deposition in the glomerular mesangial area, where TG2 is significantly enhanced. Therefore, identification of glomerular TG2 substrates is the first step in elucidating the role of TG2 as a crosslinking enzyme during disease progression. To clarify potential glomerular TG2 substrates, and to establish a procedure for substrate identification, we attempted to identify those molecules using normal mouse glomeruli. Extracts from mouse glomerular and non-glomerular fractions were treated with our established biotin-labeled substrate peptide, which specifically crosslinks to the lysine-donor substrates depending on TG2 activity. Peptide-incorporated proteins were then purified using avidin resin and identified via mass spectrometry. In parallel, we performed the identification using corresponding samples from TG2 knockout mice. Consequently, potential TG2 substrates were separately identified in glomerular and non-glomerular fractions. They were mainly identified as novel TG2 substrates and partly include the well-known substrates. These results potentially provide novel insights into the mechanism underlying IgA nephropathy and may help elucidate the physiological functions of TG2.

BACKGROUND: 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. METHODS: 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 < 9.5 mg/dL, (4) serum phosphate level 4.0-6.0 mg/dL, and (5) serum intact parathyroid hormone (PTH) level ≥ 60 pg/mL. Study patients will be randomized 1:1 to receive alfacalcidol alone or in combination with LC. The initial dose of alfacalcidol will be 0.25-0.5 µg once a day according to serum adjusted calcium level. The initial dose of LC will be 250 mg once a day. We will measure serum intact and C-terminal FGF23 at 0, 4, 8, 12, 24, and 52 weeks. The primary outcome will be serum FGF23 level at 24 weeks compared with baseline. DISCUSSION: This study aims to determine whether low-dose oral VDRA increases serum FGF23 level and whether the combination of VDRA and LC inhibits this increase. The results will be useful in the management of CKD-mineral and bone disorder in predialysis patients. TRIAL REGISTRATION: UMIN000030503. Registered 20 January 2018.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

RATIONALE: Immunoglobulin G4 related disease (IgG4-RD) rarely coexists with other autoimmune diseases, though we had a patient whose primary clinical problem was shifted from IgG4-RD to systemic lupus erythematosus (SLE) after gastrectomy. The present paper aimed to report pathological findings and clinical course of the patient. PATIENT CONCERNS: The patient was a male aged 74 years old with gastric cancer characterized by the following symptoms: Raynaud phenomenon, polyarthralgia, and swollen parotid glands on both sides. Before gastrectomy, laboratory examination results showed renal dysfunction, hypocomplementemia, antinuclear antibodies (ANAs) positivity, and elevated serum IgG and IgG4 levels. DIAGNOSIS: Based on postoperative renal biopsy showing severe plasma cell infiltration with tubulointerstitial fibrosclerosis, the patient was diagnosed with IgG4-RD. Despite significant improvement in renal function and reduction in parotid gland swelling during the postoperative follow-up period, after 7 months of the gastrectomy, anti-DNA antibody levels were increased and serositis was detected, which indicated the onset of SLE. IgG4-type ANA were also detected in the sera of the patient. INTERVENTIONS: Treatment by oral prednisolone at 30 mg/day was initiated. OUTCOMES: Pericardial fluid, pleural effusions, and thickening of the gallbladder wall improved after 3 months of treatment according to computed tomography. LESSONS: This study presented a rare case of comorbidity, wherein the patient's primary problem progressed from IgG4-type ANA-positive IgG4-RD to SLE after excision of gastric cancer.

INTRODUCTION: As glomerular filtration rate (GFR) decreases, serum phosphate level increases. Previous reports indicated that serum phosphate level was associated with mortality in patients on dialysis. However, few reports have examined the association using dialysis initiation as the baseline period. METHODS: This was a multicenter prospective cohort analysis including 1492 patients. Patients were classified into four quartiles based on the serum phosphate level at dialysis initiation, with Q1 being the lowest and Q4 the highest. All-cause mortality after dialysis initiation was compared using the log-rank test. The propensity score represented the probability of being assigned to group Q1 or Q2-4. All-cause mortality was compared in propensity score-matched patients by using the log-rank test for Kaplan-Meier curves. All-cause mortality of Q1 was compared with that for Q2-4 using multivariate Cox proportional hazard regression analysis. All-cause mortality was also determined among stratified groups with or without use of phosphate binders. RESULTS: Significant differences in cumulative survival rates were observed between the four groups (p < .001). After propensity score-matching, mortality was significantly higher in the Q1 group than the Q2-4 group (p = .046). All-cause mortality was significantly higher in the Q1 group after adjustment for history of CAD (hazard ratio [HR] = 0.76, 95% confidence interval [CI]: 0.58 - 1.00, p = .048). However, there was no significant difference between the two groups after adjustment for estimated GFR. CONCLUSION: The serum phosphate level at the time of dialysis initiation was associated with all-cause mortality. However, the serum phosphate level was dependent on the renal function.

Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention is necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search.

Background: Diabetic nephropathy is a leading cause of end-stage kidney disease in the world. Although various types of treatment for diabetes, hypertension and dyslipidemia have improved prognosis and quality of life in patients with diabetic nephropathy, there still exist some diabetic patients with severe proteinuria showing poor prognosis. This clinical trial, LICENSE, aims to confirm the impact of LDL apheresis on proteinuria exhibiting hyporesponsiveness to treatment. Methods: This ongoing trial is a multicenter, prospective study of diabetic patients with severe proteinuria. The objective is to examine the impact of LDL apheresis on proteinuria in patients with diabetic nephropathy. The other subject is to investigate safety of LDL apheresis in these patients. Results: The subjects consist of diabetic patients with serum creatinine (Cr) levels below 2 mg/dL who present severe proteinuria above 3 g/g Cr or 3 g/day and LDL cholesterol above 120 mg/dL. The target number of registered patients will be 35 patients. Urinary protein excretion and renal function will be observed for 24 weeks after the treatment of LDL apheresis. Conclusion: This study will determine the effectiveness and safety of LDL apheresis for diabetic nephropathy patients with severe proteinuria and dyslipidemia.

BACKGROUND: The Japanese classification of diabetic nephropathy reflects the risks of mortality, cardiovascular events and kidney prognosis and is clinically useful. Furthermore, pathological findings of diabetic nephropathy are useful for predicting prognoses. In this study, we evaluated the characteristics of pathological findings in relation to the Japanese classification of diabetic nephropathy and their ability to predict prognosis. METHODS: The clinical data of 600 biopsy-confirmed diabetic nephropathy patients were collected retrospectively from 13 centers across Japan. Composite kidney events, kidney death, cardiovascular events, all-cause mortality, and decreasing rate of estimated GFR (eGFR) were evaluated based on the Japanese classification of diabetic nephropathy. RESULTS: The median observation period was 70.4 (IQR 20.9-101.0) months. Each stage had specific characteristic pathological findings. Diffuse lesions, interstitial fibrosis and/or tubular atrophy (IFTA), interstitial cell infiltration, arteriolar hyalinosis, and intimal thickening were detected in more than half the cases, even in Stage 1. An analysis of the impacts on outcomes in all data showed that hazard ratios of diffuse lesions, widening of the subendothelial space, exudative lesions, mesangiolysis, IFTA, and interstitial cell infiltration were 2.7, 2.8, 2.7, 2.6, 3.5, and 3.7, respectively. Median declining speed of eGFR in all cases was 5.61 mL/min/1.73 m2/year, and the median rate of declining kidney function within 2 years after kidney biopsy was 24.0%. CONCLUSIONS: This study indicated that pathological findings could categorize the high-risk group as well as the Japanese classification of diabetic nephropathy. Further study using biopsy specimens is required to clarify the pathogenesis of diabetic kidney disease.

BACKGROUND: Nephrosclerosis is an increasingly reason for dialysis in Japan. However, kidney biopsy specimens for hypertensive nephrosclerosis are very limited; thus, the pathologic evaluation of hypertensive nephrosclerosis currently remains unclear. METHODS: Clinical and pathologic data of a total of 184 biopsy-confirmed hypertensive nephrosclerosis patients were collected from 13 centers throughout Japan. Seven pathological findings were assessed in this study. The outcomes of interest for this study were dialysis, composite kidney events, cardiovascular events, and all-cause mortality. RESULTS: The Green and Yellow (G&Y), Orange, and Red groups of the chronic kidney diseases (CKD) heat map contained 36, 57, and 91 cases, respectively. The mean observation period was 7.3 ± 5.2 (median, IQR; 6.1, 2.6-9.7) years. Global glomerulosclerosis (GScle), interstitial fibrosis and tubular atrophy (IFTA), arteriolar hyalinosis in Red exhibited higher scores than those in G&Y and Orange. The incidence rates of the composite kidney end points in 100 person-years for the G&Y, Orange, and Red groups were 1.42, 2.16, and 3.98, respectively. In the univariate Cox analysis for the composite kidney end points, GScle, IFTA and interstitial cell infiltration exhibited statistically significant high hazard ratios (1.18, 1.84, 1.69, respectively). However, after adjustment for clinical and medication data, the Red group in the CKD heat map category was risk factor for the composite kidney end points (HR 9.51). CONCLUSIONS: In summary, although pathologic findings had minor impacts on the prediction of composite outcomes in this study, the clinical stage of the CKD heat map is a good predictor of composite kidney events.

Accumulation of amyloid-β protein (Aβ) in the brain causes cognitive impairment in Alzheimer’s disease. We hypothesized that an extracorporeal system that rapidly removed Aβ from the blood may accelerate Aβ drainage from the brain. We previously reported that dialyzers remove blood Aβs effectively, mainly by adsorption on the inner surfaces of the hollow fibers, resulting in lower Aβ accumulation in the brains of patients undergoing hemodialysis than the controls without hemodialysis. The aim of the present study was to create a more convenient and effective blood Aβ removal system using adsorptive filtration, in which the filtrate returned to the body. Filtration from inside to outside of the fibers may enhance the adsorption of plasma Aβs on the surface of micropores inside the hollow fiber walls. Hence, pool solutions of 4 ng/mL synthetic Aβ1–40 and Aβ1–42 peptides (300 mL) or human plasma (1000 mL of 250–346 pg/mL Aβ1–40 and 30–48 pg/mL Aβ1–42) were circulated through polysulfone dialyzers at a flow rate of 50 mL/min to evaluate an adsorptive filtration system. The rates of Aβ reduction from the pool solutions significantly increased along with the filtration rates. A filtration rate of &gt 1 mL/min, preferably 5–10 mL/min resulted in an 80–100% reduction of Aβs within 30 min of circulation. The rates of Aβs passing through the membrane walls were maintained around 0% for plasma Aβs during circulation. Thus, our adsorptive filtration systems may be useful for removing blood Aβs for patients with Alzheimer’s disease.

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 multicentre prospective cohort analysis including 1102 patients. Patients were classified into four groups based on resting heart rate just before starting the first dialysis session: <60/min; 60-79/min; 80-100/min; and ≥101/min. All-cause mortality, cardiovascular (CV) related mortality, and incidences of CV events after dialysis initiation were compared using the log-rank test. All-cause mortality rates for patients with heart rates <60, 60-79, and ≥101/min were compared to those for patients with heart rates 80-100/min, using multivariate Cox proportional hazard regression analysis. Moreover, we compared the outcomes among patients without use of β-blocker or heart failure symptom at the first dialysis session. RESULTS: Significant differences were observed in the all-cause mortality rates among the four groups (P = 0.007). Multivariate analysis revealed that all-cause mortality was significantly higher in patients with heart rate ≥ 101/min than in patients with heart rate 80-100/min (hazard ratio [HR] = 2.30, 95% confidence interval [CI]: 1.25-4.23). Subgroup analysis showed that among patients without use of b-blocker or heart failure symptom, all-cause mortality rates for those with heart rates ≥101/min were significantly higher than in patients with heart rate 80-100/min (HR = 2.98, 95% CI: 1.51-5.88, HR = 3.65, 95% CI: 1.59-8.36, respectively). CONCLUSION: The resting heart rate just before starting the first dialysis session was associated with all-cause mortality after dialysis initiation.

BACKGROUND: Aortic stenosis (AS) is common in patients on dialysis as well as in the general population. AS leads to difficulty with dialysis therapy because of unstable conditions such as intradialytic hypotension due to low cardiac output. However, the precise morbidity rates and risk factors of AS in patients on dialysis are unknown. Moreover, there are no large-scale observational studies regarding the association between AS in patients on dialysis and mortality. Therefore, we will investigate whether morbidity of AS in patients on dialysis is associated with mortality. METHODS: This is a multicenter prospective cohort analysis in the Tokai region of Japan. The 75 participating centers in this study will enroll approximately 2400 patients during 12 months, with or without AS. We started enrollment in July 2017 and will follow patents until June 2023. Transthoracic echocardiography will be performed to evaluate aortic valve. Parameters used for evaluation of aortic valve are mean pressure gradient between left ventricle and ascending aorta, aortic valve area, and maximum aortic jet velocity. We will diagnose AS using the criteria based on the 2014 American Heart Association/ American College of Cardiology Guideline. We will also perform transthoracic echocardiography at 12, 24, 36, 48, and 60 months. Survival prognosis and CV events will be determined at the end of June 2019, 2020, 2021, 2022, and 2023. Development of AS will be also evaluated as new onset or annual change in AS parameters. We will classify patients based on the presence or absence of AS and the stages of AS and will compare outcomes. Study outcomes will include the following: 1) all-cause mortality rates; 2) incidence of cardiovascular (CV) events; 3) CV-related mortality rates; 4) infection-related mortality rates; 5) new onset or development of AS. DISCUSSION: We will consider the following hypotheses in this study, among others: The prevalence of AS is higher in dialysis patients; new onset and development of AS are associated with factors that are specific for dialysis, such as hyperphosphatemia, hyperparathyroidism, and medication; and outcomes in AS patients are poorer than in patients without AS at baseline. TRIAL REGISTRATION: UMIN000026756 , Registered March 29 2017.

BACKGROUND: 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. METHODS: 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. RESULTS: Significant differences were observed in all-cause mortality among the four groups (p < 0.001). Multivariate analysis revealed that all-cause mortality was significantly higher in Q4 than in Q1 [hazard ratio (HR) = 1.82, 95% confidence interval (CI) 1.24-2.67, p = 0.002]. The increase in BUN/Cr ratio was positively associated with mortality (HR 1.04, 95% CI 1.02-1.06, p = 0.002). The sensitivity and specificity of BUN/Cr ratio for 180, 365, 730, and 1095 days mortality ranged between 0.60-0.72 and 0.59-0.71, respectively. The area under the curve of BUN/Cr for all-cause mortality was the highest among the renal parameters. CONCLUSION: The BUN/Cr ratio at the time of initiation of dialysis was associated with all-cause mortality.

Background: The clinical and pathologic manifestations of nephropathy due to type 2 diabetes are diverse, but large-scale pathologic studies with long-term observations are limited. Methods: Kidney biopsies and clinical data of 600 patients with type 2 diabetes were collected retrospectively from 13 centres across Japan. Thirteen pathologic findings (nine glomerular lesions, two interstitial lesions and two vascular lesions) were clearly defined and scored. Results: During the observation period, there were 304 composite kidney events [dialysis, doubling of creatinine or reduction of estimated glomerular filtration rate (eGFR) by half], 31 instances of chronic kidney disease (CKD) G5D, 76 cardiovascular events and 73 deaths. The mean observation period was 72.4 months. The distribution of CKD heat map categories for the 600 patients was 103 green or yellow, 149 orange and 348 red. Even in the cases in the green and yellow category, diffuse lesions (81.6%), polar vasculosis (42.6%) and subendothelial space widening (35.1%) were commonly detected. Cox proportional hazard analysis revealed that the presence of nodular lesions [hazard ratio (HR) 21.1, 95% confidence interval (CI) 5.3-84.6], exudative lesions (HR 5.1, 95% CI 1.3-20.3) and mesangiolysis (HR 7.6, 95% CI 2.0-28.8) in cases in the green and yellow category were associated with significantly great impact on composite kidney events after adjustment for clinical risk factors. Conclusions: This nationwide study on kidney biopsy of 600 cases with type 2 diabetes revealed that pathologic findings (presence of nodular lesions, exudative lesions and mesangiolysis) were strong predictors of kidney events in low-risk patients.

Mannosylation in the endoplasmic reticulum is a key process for synthesizing various glycans. Guanosine diphosphate mannose (GDP-Man) and dolichol phosphate-mannose serve as donor substrates for mannosylation in mammals and are used in N-glycosylation, O-mannosylation, C-mannosylation, and the synthesis of glycosylphosphatidylinositol-anchor (GPI-anchor). Here, we report for the first time that low-abundant uridine diphosphate-mannose (UDP-Man), which can serve as potential donor substrate, exists in mammals. Liquid chromatography-mass spectrometry (LC-MS) analyses showed that mouse brain, especially hypothalamus and neocortex, contains higher concentrations of UDP-Man compared to other organs. In cultured human cell lines, addition of mannose in media increased UDP-Man concentrations in a dose-dependent manner. These findings indicate that in mammals the minor nucleotide sugar UDP-Man regulates glycosylation, especially mannosylation in specific organs or conditions.

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. (C) 2017 S. Karger AG, Basel

Background: Precise understanding of kidney disease activity is needed to design therapeutic strategies. CD147/basigin is involved in the pathogenesis of acute kidney injury and renal fibrosis through inflammatory cell infiltration. The present study examined the clinical relevance of CD147 in biopsy-proven kidney diseases that lead to the progression of chronic kidney disease. Methods: Kidney biopsy specimens and plasma and urine samples were obtained from patients with kidney diseases, including IgA nephropathy (IgAN), Henoch–Schönlein purpura nephritis (HSPN), diabetic kidney disease (DKD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN), who underwent renal biopsy between 2011 and 2014. Plasma and urinary CD147 levels were measured and evaluated for their ability to reflect histological features. Disease activity of IgAN tissues was evaluated according to the Oxford classification and the Japanese histological grading system. Results: In biopsy tissues, CD147 induction was detected in injured lesions representing renal inflammation. Plasma CD147 values correlated with eGFR in patients with inflammation-related kidney diseases such as IgAN, HSPN, and DKD. Particularly in IgAN patients, plasma CD147 levels were correlated with injured regions comprising more than 50% of glomeruli or with tubular atrophy/interstitial injury in biopsy tissues. Proteinuria showed a closer correlation with urinary values of CD147 and L-FABP. Of note, plasma and urinary CD147 levels showed a strong correlation with eGFR or proteinuria, respectively, only in DKD patients. Conclusion: Evaluation of plasma and urinary CD147 levels might provide key insights for the understanding of the activity of various kidney diseases.

Background: There is increased interest in surrogate endpoints for clinical trials of chronic kidney disease. Methods: In this nationwide observational study of 456 patients with type 2 diabetes and clinically suspected diabetic nephropathy followed for a median of 4.2 years, we evaluated the association between estimated glomerular filtration rate (eGFR) and albuminuria at baseline or during follow-up and risk of ESRD. Results: Low eGFR (&lt 60 mL/min/1.73 m2) and macroalbuminuria at enrollment were independently associated with risk of ESRD. In patients with macroalbuminuria, both ≤−50% change and −50 to −30% change in eGFR over 1 and 2 years were predictive of ESRD. The higher cut point (≥50% decline in eGFR) was more strongly predictive but less common. Remission of macroalbuminuria to normo-/microalbuminuria at 1 and 2 years was associated with a lower incidence of ESRD than no remission however, it was not a determinant for ESRD independently of initial eGFR and initial protein-to-creatinine ratio. Conclusion: These results suggest that a ≥30% decline in eGFR over 1 or 2 years adds prognostic information about risk for ESRD in patients with type 2 diabetes and macroalbuminuria, supporting the consideration of percentage decline in eGFR as a surrogate endpoint among macroalbuminuric cases in type 2 diabetes. On the other hand, our study suggests that additional analyses on the relationship between remission of macroalbuminuria and risk of ESRD are needed in type 2 diabetes.

Background: Targeted proteomics, which involves quantitative analysis of targeted proteins using selected reaction monitoring (SRM) mass spectrometry, has emerged as a new methodology for discovery of clinical biomarkers. In this study, we used targeted serum proteomics to identify circulating biomarkers for prediction of disease activity and organ involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: A large-scale SRM assay targeting 135 biomarker candidates was established using a triple-quadrupole mass spectrometer coupled with nanoflow liquid chromatography. Target proteins in serum samples from patients in the active and remission (6 months after treatment) stages were quantified using the established assays. Identified marker candidates were further validated by enzyme-linked immunosorbent assay using serum samples (n = 169) collected in a large-cohort Japanese study (the RemIT-JAV-RPGN study). Results: Our proteomic analysis identified the following proteins as biomarkers for discriminating patients with highly active AAV from those in remission or healthy control subjects: tenascin C (TNC), C-reactive protein (CRP), tissue inhibitor of metalloproteinase 1 (TIMP1), leucine-rich alpha-2-glycoprotein 1, S100A8/A9, CD93, matrix metalloproteinase 9, and transketolase (TKT). Of these, TIMP1 was the best-performing marker of disease activity, allowing distinction between mildly active AAV and remission. Moreover, in contrast to CRP, serum levels of TIMP1 in patients with active AAV were significantly higher than those in patients with infectious diseases. The serum levels of TKT and CD93 were higher in patients with renal involvement than in those without, and they predicted kidney outcome. The level of circulating TNC was elevated significantly in patients with lung infiltration. AAV severity was associated with markers reflecting organ involvement (TKT, CD93, and TNC) rather than inflammation. The eight markers and myeloperoxidase (MPO)-ANCA were clustered into three groups: MPO-ANCA, renal involvement (TKT and CD93), and inflammation (the other six markers). Conclusions: We have identified promising biomarkers of disease activity, disease severity, and organ involvement in AAV with a targeted proteomics approach using serum samples obtained from a large-cohort Japanese study. Especially, our analysis demonstrated the effectiveness of TIMP1 as a marker of AAV activity. In addition, we identified TKT and CD93 as novel markers for evaluation of renal involvement and kidney outcome in AAV.

Background Malaria is an important tropical disease and has remained a serious health problem in many countries. One of the critical complications of malarial infection is renal injury, such as acute renal failure and chronic glomerulopathy. Few animal models of nephropathy related to malarial infection have been reported. Therefore, we developed and investigated a novel malarial nephropathy model in mice infected by murine malaria parasites. Methods NC mice and C57BL/6J mice were infected with Ttwo different murine malaria parasites, Plasmodium (P.) chabaudi AS and P. yoelii 17X. After the infection, renal pathology and blood and urinary biochemistry were analyzed. Results NC mice infected by the murine malaria parasite P. chabaudi AS, but not P. yoelii 17X, developed mesangial proliferative glomerulonephritis with endothelial damage, and decreased serum albumin concentration and increased proteinuria. These pathological changes were accompanied by deposition of immunoglobulin G and complement component 3, mainly in the mesangium until day 4 and in the mesangium and glomerular capillaries from day 8. On day 21, renal pathology developed to focal segmental sclerosis according to light microscopy. In C57BL/6J mice, renal injuries were not observed from either parasite infection. Conclusion The clinical and pathological features of P. chabaudi AS infection in NC mice might be similar to quartan malarial nephropathy resulting from human malaria parasite P. malariae infection. The NC mouse model might therefore be useful in analyzing the underlying mechanisms and developing therapeutic approaches to malaria-related nephropathy.

Background The mortality and morbidity associated with acute kidney injury (AKI) remains high, despite advances in interventions. A multifunctional heparin-binding growth factor, midkine (MK), is involved in the pathogenesis of ischemic kidney injury. However, the clinical relevance of MK has not yet been elucidated. The present study investigated whether urinary MK can serve as a novel biomarker of AKI. Methods We initially compared the predictive value of MK with other urinary biomarkers, including N-acetyl-beta-D-glucosaminidase (NAG), interleukin (IL)-18, and neutrophil gelatinase-associated lipocalin (NGAL), for the detection and differential diagnosis of established AKI (549 patients). Subsequently, the reliability of MK for the early detection of AKI was prospectively evaluated in 40 patients undergoing elective abdominal aortic aneurysm surgery. Urine samples were obtained at baseline, the period of aortic cross-clamping and declamping, the end of the surgery, and on post-operative day 1. Results The areas under the receiver operating characteristic curves for the diagnosis of AKI in various kidney diseases were 0.88, 0.70, 0.72, and 0.84 for MK, NAG, IL-18, and NGAL, respectively. When the optimal cutoff value of urinary MK was set at 11.5 pg/mL, the sensitivity and specificity were 0.87 and 0.85, respectively. In the second study, urinary MK peaked at the period of aortic declamping, about 1 h after cross-clamping in patients with AKI. Interestingly, the rise of MK in AKI patients was very precipitous compared with other biomarker candidates. Conclusion Urinary MK was prominent in its ability to detect AKI and may allow the start of preemptive medication.

＜Key Points＞IgA腎症は健康診断などで蛋白尿や血尿を指摘されたことを契機に発見されることが多く、腎生検により確定診断される。尿蛋白量の程度、血圧値、腎機能障害の程度、組織学的障害度が腎生存率と関連する。「エビデンスに基づくIgA腎症診療ガイドライン2014」では、腎機能と尿蛋白量から、腎機能障害の進行抑制を目的とした治療介入の適応が図示されている。RAS阻害薬と副腎皮質ステロイドを中心に治療が行われる。(著者抄録)

Additional risk stratification may provide more aggressive and focalized preventive treatment to high-risk hypertensive patients according to the Japanese hypertension guidelines. We prospectively investigated the predictive value of high-sensitivity troponin I (hsTnI), both independently and in combination with N-terminal pro-B-type natriuretic peptide (NT-proBNP), for incident heart failure (HF) in high-risk hypertensive patients with preserved left ventricular ejection fraction (LVEF). Baseline hsTnI and NT-proBNP levels and echocardiography data were obtained for 493 Japanese hypertensive outpatients (mean age, 68.5 years) with LVEF ae&lt;yen&gt; 50%, no symptomatic HF, and at least one of the following comorbidities: stage 3-4 chronic kidney disease, diabetes mellitus, and stable coronary artery disease. During a mean follow-up period of 86.1 months, 44 HF admissions occurred, including 31 for HF with preserved ejection fraction (HFpEF) and 13 for HF with reduced ejection fraction (HFrEF; LVEF &lt; 50%). Both hsTnI (p &lt; 0.01) and NT-proBNP (p &lt; 0.005) levels were significant independent predictors of HF admission. Furthermore, when the patients were stratified into 4 groups according to increased hsTnI (ae&lt;yen&gt;highest tertile value of 10.6 pg/ml) and/or increased NT-proBNP (ae&lt;yen&gt;highest tertile value of 239.7 pg/ml), the adjusted relative risks for patients with increased levels of both biomarkers versus neither biomarker were 13.5 for HF admission (p &lt; 0.0001), 9.45 for HFpEF (p = 0.0009), and 23.2 for HFrEF (p = 0.003). Finally, the combined use of hsTnI and NT-proBNP enhanced the C-index (p &lt; 0.05), net reclassification improvement (p = 0.0001), and integrated discrimination improvement (p &lt; 0.05) to a greater extent than that of any single biomarker. The combination of hsTnI and NT-proBNP, which are individually independently predictive of HF admission, could improve predictions of incident HF in high-risk hypertensive patients but could not predict future HF phenotypes.

Since the Oxford Classification of IgA nephropathy (IgAN) was published in 2009, MEST scores have been increasingly used in clinical practice. Further retrospective cohort studies have confirmed that in biopsy specimens with a minimum of 8 glomeruli, mesangial hypercellularity (M), segmental sclerosis (5), and interstitial fibrosis/tubular atrophy (T) lesions predict clinical outcome. In a larger, more broadly based cohort than in the original Oxford study, crescents (C) are predictive of outcome, and we now recommend that C be added to the MEST score, and biopsy reporting should provide a MEST-C score. Inconsistencies in the reporting of M and endocapillary cellularity (E) lesions have been reported, so a web-based educational tool to assist pathologists has been developed. A large study showed E lesions are predictive of outcome in children and adults, but only in those without immunosuppression. A review of S lesions suggests there may be clinical utility in the subclassification of segmental sclerosis, identifying those cases with evidence of podocyte damage. It has now been shown that combining the MEST score with clinical data at biopsy provides the same predictive power as monitoring clinical data for 2 years; this requires further evaluation to assess earlier effective treatment intervention. The IgAN Classification Working Group has established a well-characterized dataset from a large cohort of adults and children with IgAN that will provide a substrate for further studies to refine risk prediction and clinical utility, including the MEST-C score and other factors.

Increased intracellular cyclic AMP (cAMP) in renal tubular epithelia accelerates the progression of polycystic kidney disease (PKD). Thus, decreasing cAMP levels by an adenylyl cyclase inhibitory G protein activator is considered to be an effective approach in ameliorating PKD. In fact, pasireotide (PAS) was effective in reducing disease progression in animal models of PKD. However, hyperglycemia caused by the administration of PAS is an adverse effect in its clinical use. Whereas, co-administration of octreotide (OCT) with PAS did not increase serum glucose in normal rats. In the current study, we examined the efficacy of combined treatment with OCT and PAS in PCK rats, an autosomal recessive PKD model. Four-week-old PCK males were treated with the long-acting release type of OCT, PAS, or a combination of both (OCT/PAS) for 12 weeks. After termination, serum and renal tissue were used for analyses. Kidney weight, kidney weight per body weight, renal cyst area, renal Ki67 expression, and serum urea nitrogen were significantly decreased either in the PAS or OCT/PAS group, compared with vehicle. Renal tissue cAMP content was significantly decreased by PAS or OCT/PAS treatment, but not OCT, compared with vehicle. As a marker of cellular mTOR signaling activity, renal phospho-S6 kinase expression was significantly decreased by OCT/PAS treatment compared with vehicle, OCT, or PAS. Serum glucose was significantly increased by PAS administration, whereas no difference was shown between vehicle and OCT/PAS, possibly because serum glucagon was decreased either by the treatment of OCT alone or co-application of OCT/PAS. In conclusion, since serum glucose levels are increased by the use of PAS, its combination with OCT may reduce the risk of hyperglycemia associated with PAS monotherapy against PKD progression.

Activated T cells play crucial roles in the pathogenesis of autoimmune diseases, including Lupus nephritis (LN). The activation of calcineurin/nuclear factor of activated T cells (NFAT) and STAT4 signaling is essential for T cells to perform various effector functions. Here, we identified the growth factor midkine (MK; gene name, Mdk) as a novel regulator in the pathogenesis of 2,6,10,14-tetramethylpentadecane-induced LN via activation of NFAT and IL-12/STAT4 signaling. Wild-type (MdK+/+) mice showed more severe glomerular injury than MK-deficient (Mdk(-/-)) mice, as demonstrated by mesangial hypercellularity and matrix expansion, and glomerular capillary loops with immune-complex deposition. Compared with Mdk(-/-) mice, the frequency of splenic CD69(+) T cells and T helper (Th) 1 cells, but not of regulatory T cells, was augmented in Mdk(+/+) mice in proportion to LN disease activity, and was accompanied by skewed cytokine production. MK expression was also enhanced in activated CD4(+) T cells in vivo and in vitro. MK induced activated CD4(+) T cells expressing CD69 through nuclear activation of NFAT transcription and selectively increased in vitro differentiation of naive CD4(+) T cells into Th1 cells by promoting IL-12/STAT4 signaling. These results suggest that MK serves an indispensable role in the NFAT-regulated activation of CD4(+) T cells and Th1 cell differentiation, eventually leading to the exacerbation of LN.

The Oxford Classification of IgA nephropathy does not account for glomerular crescents. However, studies that reported no independent predictive role of crescents on renal outcomes excluded individuals with severe renal insufficiency. In a large IgA nephropathy cohort pooled from four retrospective studies, we addressed crescents as a predictor of renal outcomes and determined whether the fraction of crescent-containing glomeruli associates with survival from either a &gt;= 50% decline in eGFR or ESRD (combined event) adjusting for covariates used in the original Oxford study. The 3096 subjects studied had an initial mean +/- SD eGFR of 78 +/- 29 ml/min per 1.73 m(2) and median (interquartile range) proteinuria of 1.2 (0.7-2.3) g/d, and 36% of subjects had cellular or fibrocellular crescents. Overall, crescents predicted a higher risk of a combined event, although this remained significant only in patients not receiving immunosuppression. Having crescents in at least one sixth or one fourth of glomeruli associated with a hazard ratio (95% confidence interval) for a combined event of 1.63 (1.10 to 2.43) or 2.29 (1.35 to 3.91), respectively, in all individuals. Furthermore, having crescents in at least one fourth of glomeruli independently associated with a combined event in patients receiving and not receiving immunosuppression. We propose adding the following crescent scores to the Oxford Classification: CO (no crescents); C1 (crescents in less than one fourth of glomeruli), identifying patients at increased risk of poor outcome without immunosuppression; and C2 (crescents in over one fourth of glomeruli), identifying patients at even greater risk of progression, even with immunosuppression.

Background: Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease (CVD) events, and a number of reports have shown a relationship between CKD and CVD in pre-dialysis or maintenance dialysis patients. However, few studies have reported serial observations during dialysis initiation and maintenance. Therefore, we examined whether the incidence of heart disease events differed between CKD patients with and without a history of coronary heart disease (CHD) at dialysis initiation. Methods: The subjects were patients in the 17 centers participating in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP) from October 2011 to September 2013. We excluded nine patients whose outcomes were unknown, as determined by a survey conducted at the end of March 2015. Thus, we enrolled 1,515 subjects into the study. We classified patients into 2 groups according to the history of CHD (i.e., a CHD group and a non-CHD group). Propensity scores (PS) represented the probability of being assigned to a group with or without a history of CHD. Onset of heart disease events and associated mortality and all-cause mortality were compared in PSmatched patients by using the log-rank test for Kaplan-Meier curves. Factors contributing to heart disease events were examined using stepwise multivariate Cox proportional hazards analysis. Results: There were 254 patients in each group after PS-matching. During observation, heart disease events occurred in 85 patients (33.5%) in the CHD group and 48 (18.9%) patients in the non-CHD group. The incidence was significantly higher in the CHD group (p &lt; 0.0001). The CHD group was associated with higher incidence of heart disease events (vs. the non-CHD group, hazard ratio = 1.750, 95% confidence interval = 1.160-2.639). In addition, comorbidities such as diabetes mellitus, low body mass index, and low serum high-density lipoprotein cholesterol were associated with higher incidence of events. Conclusion: History of CHD at dialysis initiation was associated with a higher incidence of heart disease events and mortality and all-cause mortality.

<p>Background: Cell-free and concentrated ascites reinfusion therapy (CART) was approved by the National Insurance Scheme in 1981 in Japan and has since been used as a treatment modality for refractory ascites. Two filtration methods may be used for CART: the internal and external pressure filtration methods. However, the precise characteristics of each method are unknown.</p><p>Methods: Ascitic fluid will be obtained by puncture from patients with refractory cancerous ascites. The quantity of fluid obtained from each patient will be divided in half, and each half will be processed using either the internal or external pressure filtration method. The primary endpoint will be the time required for the transmembrane pressure to reach 500 mmHg. The secondary endpoints will be serial changes in the weight of the ascitic and filtered fluid, serial changes in the pressure at the inlet and outlet of the filter, measurement of the components of the ascitic and filtered fluid, and observation of the filter by visual inspection and light and electron microscopy.</p><p>Conclusion: This trial may clarify the characteristics of the two filtration methods.</p><p>Trial registration: UMIN000025382.</p>

Objective: To investigate the correlation between serum 1,25-dihydroxyvitamin D (1,25D) levels and left atrial diameter (LAD) using echocardiography in pre-dialysis chronic kidney disease (CKD). Subjects and methods: From an initial population of 487 patients (109 met the exclusion criteria), a total of 378 patients with CKD stage 3a - 5 who had not undergone dialysis or kidney transplantation were included in the study. The relationship between serum 1,25D levels and LAD was examined. Moreover, factors that impacted LAD were extracted through stepwise multiple regression analyses. Results: Serum 1,25D levels correlated negatively with LAD, left ventricular end-diastolic diameter, interventricular septum thickness, end-diastolic volume, stroke volume, left ventricular mass index (LVMI), and E/e'. Stepwise multiple regression analyses revealed there was a significant relationship between serum 1,25D levels and LAD (regression coefficient = -0.070, p = 0.001). In the stratified analysis, serum 1,25D levels were associated with LAD in the LVMI &lt; 125 g/m(2) (regression coefficient = -0.067, p = 0.038) and ejection fraction (EF) &gt; 60% groups (regression coefficient = -0.080, p = 0.004). Conclusion: Serum 1,25D levels were independently associated with LAD in CKD patients; however, the association was not significant in patients with an EF &lt; 60% and LVMI &gt; 125 g/m(2).

Anti-endothelial cell antibodies (AECA) are frequently detected in patients with systemic lupus erythematosus (SLE), but their pathological role remains unclear. We recently developed a solubilized cell surface protein capture enzyme-linked immunosorbent assay (CSPELISA) to detect antibodies against membrane proteins involved in autoimmune reactions. In this study, sera from 51 patients with biopsy-proven lupus nephritis (LN), 25 with SLE without renal involvement (non-LN SLE), 42 disease control (DC) subjects, and 80 healthy control (HC) subjects were tested for IgG-and IgA-AECA for human umbilical vein endothelial cells (HUVEC) and human glomerular EC (HGEC) by using CSP-ELISA. IgG-and IgA-AECA titers were significantly higher in LN and non-LN SLE patients than in the DC or HC (P &lt; 0.001) groups. IgG-and IgA-AECA titers for HUVEC corresponded well with those for HGEC. The IgA-AECA level correlated with the SLE disease activity index and with histological evidence of active lesions (cellular proliferations, hyaline thrombi and wire loops, leukocytic infiltration, and fibrinoid necrosis) in LN patients (P &lt; 0.001). The sensitivity of IgA-AECA as a diagnostic test for histological evidence of active lesions in LN patients was 0.92, with a specificity of 0.70. The significant correlation of IgA-AECA with glomerular hypercellularity indicates that IgA-AECA are associated with endothelial damage in LN.