SOX9 and SRY binding sites on mouse mXYSRa/Enh13 enhancer redundantly regulate Sox9 expression to varying degrees.

Sox9 plays an essential role in mammalian testis formation. It has been reported that gene expression in the testes is regulated by enhancers. Among them, mXYSRa/Enh13-which is located at far upstream of the transcription start site-plays a critical role, wherein its deletion causes complete male-to-female sex reversal in mice. It has been proposed that the binding sites (BSs) of SOX9 and SRY, the latter of which is the sex determining gene on the Y chromosome, are associated with mXYSRa/Enh13. They function as an enhancer, whereby the sequences are evolutionarily conserved and in vivo binding of SOX9 and SRY to mXYSRa/Enh13 has been demonstrated previously. However, their precise in vivo functions have not been examined to date. To this end, this study generated mice with substitutions on the SOX9 and SRY BSs to reveal their in vivo functions. Homozygous mutants of SOX9 and SRY BS were indistinguishable from XY males, whereas double mutants had small testes, suggesting that these functions are redundant and that there is another functional sequence on mXYSRa/Enh13, since mXYSRa/Enh13 deletion mice are XY females. In addition, the majority of hemizygous mice with substitutions in SOX9 BS and SRY BS were female and male, respectively, suggesting that SOX9 BS contributes more to SRY BS for mXYSRa/Enh13 to function. The additive effect of SOX9 and SRY via these BSs was verified using an in vitro assay. In conclusion, SOX9 BS and SRY BS function redundantly in vivo, and at least one more functional sequence should exist in mXYSRa/Enh13.

Predictors of damage accrual in patients with antineutrophil cytoplasmic antibody-associated vasculitis: A nationwide prospective study.

OBJECTIVES: This study elucidated the prognosis and risk factors associated with damage accrual during long-term remission maintenance therapy for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We obtained data from 120 patients registered in a nationwide prospective cohort study on remission induction therapy in Japanese patients with AAV and rapidly progressive glomerulonephritis (RemIT-JAV-RPGN), who achieved remission at 24 months after treatment initiation and were followed up for additional 24 months. The primary outcome was the vasculitis damage index (VDI) score at Month 48, and the secondary outcome included risk factors associated with increased total VDI at Month 48. RESULTS: The understudied patients comprised 52 men and 68 women aged 68 ± 13 years. Between Months 25 and 48, the patients' survival rate was 95% (114/120). End-stage renal disease developed in seven patients by Month 48, and 64 cases had increased VDI. The multivariable analysis results revealed that oral prednisolone (PSL) doses at Month 24 were associated with damage accrual between Months 24 and 48. CONCLUSIONS: VDI accrual was observed in more than half of patients with AAV during maintenance therapy, and increased VDI scores were associated with oral PSL doses 24 months after initiating remission induction therapy in Japan.

Tolvaptan's Association with Low Risk of Acute Kidney Injury in Patients with Advanced Chronic Kidney Disease and Acute Decompensated Heart Failure.

INTRODUCTION: Furosemide, a loop diuretic, is often empirically used to treat acute decompensated heart failure (ADHF) initially. Conversely, decongestion using tolvaptan, an aquaretic, is thought to maintain renal function compared to furosemide. However, it has not been investigated in patients with advanced chronic kidney disease (CKD) at high risk of developing acute kidney injury (AKI). This study aimed to investigate AKI incidence using tolvaptan add-on treatment, compared to increased furosemide treatment for patients with ADHF complicated by advanced CKD. METHODS: We retrospectively studied patients with advanced CKD (estimated glomerular filtration rate [eGFR] <45 mL/min/1.73 m2) who developed ADHF under outpatient furosemide treatment. The exposure was set to tolvaptan add-on treatment, and the control was set to increased furosemide treatment. RESULTS: Of the 163 patients enrolled, 79 were in the tolvaptan group and 84 in the furosemide group. The mean age was 71.6 years, the percentage of males was 63.8%, the mean eGFR was 15.7 mL/min/1.73 m2, and patients with CKD stage G5 were 61.9%. AKI incidence was 17.7% in the tolvaptan group and 42.9% in the furosemide group (odds ratio [95% confidence interval]: 0.34 [0.13-0.86], p = 0.023 in multivariate logistic regression analysis). Persistent AKI incidence was 11.8% in the tolvaptan group and 32.9% in the furosemide group (odds ratio [95% confidence interval]: 0.34 [0.10-1.06], p = 0.066 in the multinomial logit analysis). CONCLUSION: This study suggests that tolvaptan may be better than furosemide in patients with ADHF experiencing complicated advanced CKD.

Effect of Low-Density Lipoprotein Apheresis on Quality of Life in Patients with Diabetes, Proteinuria, and Hypercholesterolemia.

INTRODUCTION: Treating diabetic nephropathy with low-density lipoprotein (LDL) apheresis reduces proteinuria and improves prognosis. However, its impact on patients' quality of life (QoL) is unclear. This study evaluated the effect of LDL apheresis on QoL in patients with diabetes, proteinuria, and hypercholesterolemia. METHODS: In this nationwide multicenter prospective study, we enrolled 40 patients with diabetes. Inclusion criteria were proteinuria (defined as an albumin/creatinine ratio ≥3 g/g), serum creatinine levels <2 mg/dL, and serum LDL ≥120 mg/dL despite drug treatment. LDL apheresis was performed 6-12 times within 12 weeks. The 36-item Short Form Health Survey (SF-36) was used to analyze QoL. RESULTS: The study enrolled 35 patients (27 men and 8 women; mean age 58.9 ± 11.9 years). A comparison of baseline SF-36 values with those at the end of the course of apheresis found an improvement in the mean physical component summary (37.9 ± 11.4 vs. 40.6 ± 10.5, p = 0.051) and a significant increase in the mean mental component summary (MCS) (49.4 ± 8.4 vs. 52.5 ± 10.9, p = 0.026). A multivariable linear regression analysis revealed a history of coronary heart disease negatively correlated with the MCS increase at the end of the course of apheresis (ß coefficient -6.935, 95% confidence interval, 13.313 to-0.556, p = 0.034). CONCLUSION: Our results suggest that LDL apheresis may improve the mental and physical QoL in patients with diabetes, proteinuria, and hypercholesterolemia.

Effects of LDL apheresis on proteinuria in patients with diabetes mellitus, severe proteinuria, and dyslipidemia.

BACKGROUND: Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria. METHODS: This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6 months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24 months after therapy initiation. RESULTS: LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6 months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls. CONCLUSION: Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia. TRIAL REGISTRATION: Trial registration number: jRCTs042180076.

Relationship between selection of dosage forms of vitamin D receptor activators and short-term survival of patients on hemodialysis.

BACKGROUND: The benefits of vitamin D receptor activators (VDRAs) for patients with chronic kidney disease are well recognized. However, the optimal criteria for patient selection, dosage forms, and duration providing the highest benefit and the least potential risk remain to be confirmed. MATERIALS AND METHODS: The study population was derived from the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis, a multicenter prospective cohort study of 1520 incident dialysis patients. According to the VDRA usage status in March 2015 (interim report), the 967 patients surviving after March 2015 were classified into three groups: without VDRA (NV, n = 177), oral VDRA (OV, n = 447), and intravenous VDRA (IV, n = 343). Mortality rates were compared using the log-rank test, and factors contributing to all-cause mortality were examined using both univariate and multivariate Cox proportional hazard regression analyses. RESULTS: There were 104 deaths (NV, n = 27; OV, n = 53; IV, n = 24) during the follow-up period (1360 days, median), and significant differences in cumulative survival rates were observed between the three groups (p = 0.010). Moreover, lower all-cause mortality was associated with IV versus NV (hazard ratio, 0.46 [95% confidence interval 0.24-0.89]; p = 0.020). CONCLUSION: This study demonstrated the impact of the VDRA dosage form on the short-term survival of incident hemodialysis patients during the introduction period. Our results suggest that relatively early initiation of intravenous VDRA in patients beginning hemodialysis may have some clinical potential.

Extreme hyperuricemia is a risk factor for infection-related deaths in incident dialysis patients: a multicenter prospective cohort study.

INTRODUCTION: There are few studies on the association between serum uric acid (UA) level and mortality in incident dialysis patients. We aimed to clarify whether the serum UA level at dialysis initiation is associated with mortality during maintenance dialysis. METHODS: We enrolled 1486 incident dialysis patients who participated in a previous multicenter prospective cohort study in Japan. We classified the patients into the following five groups according to their serum UA levels at dialysis initiation: G1 with a serum UA level <6 mg/dL; G2, 6.0-8.0 mg/dL; G3, 8.0-10.0 mg/dL; G4, 10.0-12.0 mg/dL; and G5, ≥12.0 mg/dL. We created three models (Model 1: adjusted for age and sex, Model 2: adjusted for Model 1 + 12 variables, and Model 3: stepwise regression adjusted for Model 2 + 13 variables) and performed a multivariate Cox proportional hazard regression analysis to examine the association between the serum UA level and outcomes, including infection-related mortality. RESULTS: Hazard ratios (HRs) were calculated relative to the G2, because the all-cause mortality rate was the lowest in G2. For Models 1 and 2, the all-cause mortality rate was significantly higher in G5 than in G2 (HR: 1.63, 95% confidence interval [CI]: 1.14-2.33 and HR: 1.78, 95% CI: 1.19-2.68, respectively). For Models 1, 2, and 3, the infection-related mortality rate was significantly higher in G5 than in G2 (HR: 2.75, 95% CI: 1.37-5.54, HR: 3.09, 95% CI: 1.45-6.59, HR: 3.37, and 95% CI: 1.24-9.15, respectively). CONCLUSIONS: Extreme hyperuricemia (serum UA level ≥12.0 mg/dL) at dialysis initiation is a risk factor for infection-related deaths.

Oral ferrous citrate or ferrous sulfate use during predialysis may reduce serum phosphate level at dialysis initiation
.

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.

Prognosis of pulmonary fibrosis presenting with a usual interstitial pneumonia pattern on computed tomography in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody-related nephritis: a retrospective single-center study.

BACKGROUND: Myeloperoxidase anti-neutrophil cytoplasmic antibody-related nephritis (MPO-ANCA nephritis) is occasionally accompanied by lung abnormalities such as pulmonary fibrosis. However, the clinical features of pulmonary fibrosis in patients with MPO-ANCA nephritis have not been well documented. This study was performed to compare the prognosis of a usual interstitial pneumonia (UIP) pattern of lung fibrosis in patients with MPO-ANCA nephritis with the prognosis of idiopathic pulmonary fibrosis (IPF). METHODS: We retrospectively reviewed the medical records of 126 patients with MPO-ANCA nephritis and identified 31 with a UIP pattern of lung fibrosis on high-resolution or thin-slice computed tomography (CT). We compared the characteristics and prognosis of these patients with those of 32 patients with IPF. In 18 patients from both groups, we assessed and compared the decline in lung volume over time using three-dimensional (3D) CT images reconstructed from thin-section CT data. RESULTS: The numbers of male and female patients were nearly equal among patients with MPO-ANCA nephritis exhibiting a UIP pattern; in contrast, significant male dominancy was observed among patients with IPF (p = 0.0021). Significantly fewer smokers were present among the patients with MPO-ANCA nephritis with a UIP pattern than among those with IPF (p = 0.0062). There was no significant difference in the median survival time between patients with MPO-ANCA nephritis with a UIP pattern (50.8 months) and IPF (55.8 months; p = 0.65). All patients with IPF in this cohort received antifibrotic therapy (pirfenidone or nintedanib). Almost half of the deaths that occurred in patients with MPO-ANCA nephritis with a UIP pattern were caused by non-respiratory-related events, whereas most deaths in patients with IPF were caused by respiratory failure such as acute exacerbation. In the 3D CT lung volume analyses, the rate of decline in lung volume was equivalent in both groups. CONCLUSIONS: MPO-ANCA nephritis with a UIP pattern on CT may have an unfavorable prognosis equivalent to that of IPF with a UIP pattern treated with antifibrotic agents.

Ratio of blood urea nitrogen to serum creatinine at initiation of dialysis is associated with mortality: a multicenter prospective cohort study.

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.

Effect of combined vitamin D receptor activator and lanthanum carbonate on serum fibroblast growth factor 23 level in predialysis patients (CVD-LAF study): design and method.

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.

Impact of high mortality in incident dialysis patients due to hypertensive nephrosclerosis: a multicenter prospective cohort study in Aichi, Japan.

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.

Association between resting heart rate just before starting the first dialysis session and mortality: A multicentre prospective cohort study.

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 ß-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.

Aortic stenosis is a risk factor for all-cause mortality in patients on dialysis: a multicenter prospective cohort analysis.

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.

Adsorptive filtration systems for effective removal of blood amyloid ß: a potential therapy for Alzheimer's disease.

Accumulation of amyloid-ß protein (Aß) in the brain causes cognitive impairment in Alzheimer's disease. We hypothesized that an extracorporeal system that rapidly removed Aß from the blood may accelerate Aß drainage from the brain. We previously reported that dialyzers remove blood Aßs effectively, mainly by adsorption on the inner surfaces of the hollow fibers, resulting in lower Aß 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 Aß 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 Aßs on the surface of micropores inside the hollow fiber walls. Hence, pool solutions of 4 ng/mL synthetic Aß1-40 and Aß1-42 peptides (300 mL) or human plasma (1000 mL of 250-346 pg/mL Aß1-40 and 30-48 pg/mL Aß1-42) were circulated through polysulfone dialyzers at a flow rate of 50 mL/min to evaluate an adsorptive filtration system. The rates of Aß reduction from the pool solutions significantly increased along with the filtration rates. A filtration rate of > 1 mL/min, preferably 5-10 mL/min resulted in an 80-100% reduction of Aßs within 30 min of circulation. The rates of Aßs passing through the membrane walls were maintained around 0% for plasma Aßs during circulation. Thus, our adsorptive filtration systems may be useful for removing blood Aßs for patients with Alzheimer's disease.

Serum phosphate level at initiation of dialysis is associated with all-cause mortality: a multicenter prospective cohort study.

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.

Combination of high-sensitivity troponin I and N-terminal pro-B-type natriuretic peptide predicts future hospital admission for heart failure in high-risk hypertensive patients with preserved left ventricular ejection fraction.

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 ≥ 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 <50%). Both hsTnI (p < 0.01) and NT-proBNP (p < 0.005) levels were significant independent predictors of HF admission. Furthermore, when the patients were stratified into 4 groups according to increased hsTnI (≥highest tertile value of 10.6 pg/ml) and/or increased NT-proBNP (≥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 < 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 < 0.05), net reclassification improvement (p = 0.0001), and integrated discrimination improvement (p < 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.

Relationship between history of coronary heart disease at dialysis initiation and onset of events associated with heart disease: a propensity-matched analysis of a prospective cohort study.

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 PS-matched 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 < 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. TRIAL REGISTRATION: UMIN 000007096 . Registered 18 January 2012.

Association between 1,25-dihydroxyvitamin D and left atrial diameter in pre-dialysis chronic kidney disease patients
.

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 < 125 g/m2 (regression coefficient = -0.067, p = 0.038) and ejection fraction (EF) ≥ 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 < 60% and LVMI > 125 g/m2.