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.

Relationship between serum sodium level at dialysis initiation and all-cause mortality.

BACKGROUND: Hyponatremia is a common electrolyte disorder in patients with chronic kidney disease. In addition, hyponatremia is associated with mortality in patients with chronic kidney disease, including those on dialysis. However, few studies have examined this relationship in patients with incident dialysis. METHODS: We used a database of multicenter prospective cohort studies that included 1520 incident dialysis patients. The baseline was set at the time of dialysis initiation. The enrolled patients were classified into five groups according to their serum sodium levels (< 130 mEq/L, 130-134 mEq/L, 135-139 mEq/L, 140-144 mEq/L, and ≥ 145 mEq/L). Multivariate Cox proportional hazards analysis was conducted to determine factors associated with all-cause mortality. RESULTS: A total of 392 all-cause deaths occurred during the follow-up period. The ultrafiltration volume per body weight during the first dialysis session was more significant in the groups with the lowest and highest sodium levels. The percentage of patients using loop diuretics and thiazide was higher in the group with lower sodium levels (< 130 mEq/L and 130-134 mEq/L). All-cause mortality was significantly different among the five groups (p = 0.025). Multivariate analysis indicated that all-cause mortality was significantly higher in the group with the lowest sodium level compared to the group with a serum sodium level of 135-139 mEq/L (hazard ratio: 1.61, 95% confidence interval: 1.04-2.49). CONCLUSION: Hyponatremia of < 130 mEq/L at dialysis initiation was significantly associated with all-cause mortality. We considered the results relevant to underlying conditions, including cardiovascular disease and medications.

Prescription rate of erythropoietin-stimulating agents is low for patients with renal impairment under non-nephrology care in a tertiary-level academic medical center in Japan.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) and iron supplements may be prescribed appropriately under nephrology care. However, there are few reports detailing the differences in prescription rates of these therapies among clinical departments. METHODS: A total of 39,585 patients with renal impairment were enrolled from a database of 914,280 patients. Patients were selected based on an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2. There were eight clinical departments from internal medicine, including nephrology. We defined a hemoglobin level less than 11.0 g/dL as anemia and set 20% of transferrin saturation and 100 ng/mL of serum ferritin as cutoff points. We compared the prescription rates of ESAs and iron supplementation based on the hemoglobin level and iron status among the patients seen across the eight clinical departments. RESULTS: The lower the eGFR, the more the number of patients seen under nephrology care. The rates of patients with no prescription were 52.3, 39.9, 45.9, and 54.3% among those with hemoglobin levels of < 8, 8 ≤ < 9, 9 ≤ < 10, and 10 ≤ < 11 g/dL, respectively. Of the patients with less than 11.0 g/dL of hemoglobin, 77.3% were prescribed ESAs under nephrology care. Meanwhile, only 18.5 and 8.2% of patients were prescribed ESAs in clinical departments of internal medicine, other than nephrology, and non-internal medicine care, respectively. CONCLUSION: Treatment for anemia has not been sufficiently performed in patients with renal impairment under non-nephrology care in a real-world clinical setting.

Sex differences in clinical outcomes in Japanese incident dialysis patients: a prospective observational multicenter study.

BACKGROUND: A Dialysis Outcomes and Practice Patterns Study (DOPPS) has shown a one-to-one male-to-female mortality ratio, notwithstanding the statistically longer life expectancy of women in the general population. This finding contrasts with the recent report that Japanese women on dialysis treatment have a more favorable longevity. Accordingly, we further investigated the clinical procedures and outcomes to clarify the sex differences in Japanese patients undergoing dialysis treatment. METHODS: Subjects were incident dialysis patients who participated in a multicenter prospective cohort study from October 2011 to September 2013. The all-cause mortality was analyzed by a Cox proportional hazard regression model and studied separately in women and men with or without cardiovascular disease (CVD) at baseline. RESULTS: Overall, 492 (32.3%) of the 1520 test subjects were women. All-cause mortality was higher in men (28.6%) than in women (19.9%, p < 0.001). Female sex (hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.54-0.90) and history of CVD (HR: 1.51, 95% CI: 1.18-1.95) were independent predictors of all-cause mortality. In patients without CVD, female gender was strong independent contributor (HR = 0.46, 95% CI: 0.30-0.70, p < 0.001). In contrast, patients with CVD showed no difference in survival between the sexes (HR: 0.92, 95% CI: 0.67-1.24, p = 0.597). CONCLUSION: Our study demonstrated that women undergoing chronic dialysis therapy had a lower mortality risk than men. However, complication with CVD canceled out the survival advantage in Japanese women on chronic dialysis. We should reevaluate the risk of women with CVD undergoing dialysis and apply the optimal care for CVD.

Factors associated with aortic valve stenosis in Japanese patients with end-stage kidney disease.

BACKGROUND: Aortic valve stenosis (AS) has a high prevalence and poor prognosis in patients who receive maintenance dialysis. However, few large-scale observational studies in Japan have investigated patients with AS who underwent dialysis. In this study, we investigated the prevalence and factors associated with AS in Japanese patients who underwent dialysis. METHODS: In this cross-sectional analysis, we enrolled patients who underwent dialysis and transthoracic echocardiography between July 1, 2017 and June 30, 2018. Patients with a maximum aortic jet velocity (Vmax) ≥ 2.0 m/s, pressure gradient (PG) between the left ventricle and ascending aorta (mean PG) ≥ 20 mmHg, or aortic valve area (AVA) ≤ 1.0 cm2 were categorized into the AS group (G1). Patients with Vmax ≥ 3.0 m/s, mean PG ≥ 20 mmHg, or AVA ≤ 1.0 cm2 were categorized into the moderate and severe AS groups (G2). We performed multivariate logistic regression analysis and compared G1 and G2 with the non-AS group to determine the risk factors for AS. We also investigated the risk factors for aortic valve calcification, which is a pre-stage for AS. RESULTS: Of the 2,786 patients investigated, 555 (20.0%) and 193 (6.9%) were categorized into G1 and G2, respectively. Multivariate logistic regression analysis revealed that age, long-term dialysis, and elevated serum phosphorus levels were associated with AS in both the groups (p < 0.05). These factors were converted into ordinal categories, and a multivariate logistic regression analysis was performed. Patients with serum phosphorus levels measuring 5.0-5.9 mg/dL and > 6.0 mg/dL showed a higher risk of AS than those with serum phosphorus levels measuring < 4.0 mg/dL (odds ratio 2.24, p = 0.01 and odds ratio 2.66, p = 0.005, respectively). Aortic valve calcification was associated with age, long-term dialysis, diabetes mellitus, administration of vitamin D receptor activators, elevated serum calcium levels, and anemia (p < 0.05 for all). CONCLUSIONS: Patients on dialysis showed a high prevalence of AS, which was associated with age, long-term dialysis, and elevated serum phosphorus levels. TRIAL REGISTRATION: UMIN000026756 , registered on March 29, 2017.

Relationship between mortality and use of sodium bicarbonate at the time of dialysis initiation: a prospective observational study.

BACKGROUND: Patients with chronic kidney disease often experience metabolic acidosis. Whether oral sodium bicarbonate can reduce mortality in patients with metabolic acidosis has been debated for years. Hence, this study was conducted to evaluate the utility of sodium bicarbonate in patients who will undergo dialysis therapy. In this study, we investigated the effect of oral sodium bicarbonate therapy on mortality in patients with end-stage kidney disease (ESKD) initiated on dialysis therapy. METHODS: We conducted an observational study of patients when they started dialysis therapy. There were 17 centres participating in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis. Data were available on patients' sex, age, use of sodium bicarbonate, drug history, medical history, vital data, and laboratory data. We investigated whether patients on oral sodium bicarbonate for more than three months before dialysis initiation had a better prognosis than those without sodium bicarbonate therapy. The primary outcome was defined as all-cause mortality. RESULTS: The study included 1524 patients with chronic kidney disease who initiated dialysis between October 2011 and September 2013. Among them, 1030 were men and 492 women, with a mean age of 67.5 ± 13.1 years. Of these, 677 used sodium bicarbonate and 845 did not; 13.6% of the patients in the former group and 21.2% of those in the latter group died by March 2015 (p <  0.001). Even after adjusting for various factors, the use of sodium bicarbonate independently reduced mortality (p <  0.001). CONCLUSIONS: The use of oral sodium bicarbonate at the time of dialysis initiation significantly reduced all-cause mortality in patients undergoing dialysis therapy.

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.

Association of Circulatory Iron Deficiency With an Enlarged Heart in Patients With End-Stage Kidney Disease.

OBJECTIVES: High prevalence of iron deficiency (ID) and cardiomyopathy have been observed in patients with end-stage kidney disease (ESKD). Our objective was to clarify associations between ID and cardiac remodeling in patients with ESKD. DESIGN AND METHODS: A cross-sectional study was conducted using 1974 Japanese patients with ESKD at the initiation of maintenance dialysis. Levels of hemoglobin (Hb), iron status, and cardiac enlargement as assessed by the cardiothoracic ratio (CTR) were determined immediately before the first hemodialysis session. Circulatory ID was defined as transferrin saturation (TSAT) < 20%, and stored ID was defined as ferritin level <100 ng/dL. RESULTS: The mean age was 67 years. Median CTR was 54.0%. The prevalence of circulatory and stored ID was found to be 38% and 34%, respectively. CTR was higher in patients with circulatory ID than in those without. Even in ESKD patients without overhydration, significant negative association was observed between TSAT and CTR. Higher odds ratios in parallel with higher CTR categories compared with the reference category of CTR <45% were found in patients with TSAT <20% on multinomial analysis, but ferritin did not show any significant associations. The odds ratio for CTR >54% showed an upward trend in patients with TSAT <20% (odds ratio: 1.3) and <10% (odds ratio: 1.6) compared with the reference, even after adjusting for confounding variables such as Hb and ferritin. However, that phenomenon was eliminated by adding usage of an iron agent. CONCLUSIONS: Circulatory ID is closely associated with an enlarged heart independent of ferritin and Hb. Iron supplementation in the predialysis phase of chronic kidney disease may prevent cardiac remodeling independent of Hb level in patients chronic kidney disease.

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.

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.

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.

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.

Unfavorable effects of history of volume overload and late referral to a nephrologist on mortality in patients initiating dialysis: a multicenter prospective cohort study in Japan.

BACKGROUND: Patients with late referral and positive history of volume overload may have a poor prognosis after initiating dialysis due to insufficient and/or inadequate management of complications of renal failure and the lack of better dialysis preparation. Little is known about the influence of the relationship between history of volume overload and late referral on prognosis. METHODS: We analyzed 1475 patients who had initiated dialysis for the first time from October 2011 to September 2013. late referral was defined as referral to a nephrologist < 3 months before dialysis initiation. The major outcomes were all-cause death and deaths due to cardiovascular diseases (CVD). The impact of late referral and history of volume overload on all-cause mortality was assessed by Cox proportional hazards models. RESULTS: Among 1475 patients, the mean patient age was 67.5 years. During the median follow-up of 2.2 years, 260 deaths occurred; 99 were due to CVD. Cox proportional hazards models demonstrated that late referral (adjusted hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.00-1.82) and history of volume overload (adjusted HR, 1.39; 95% CI, 1.06-1.81) were risk factors for all-cause mortality. Furthermore, late referral coexisting was associated with a history of volume overload increased mortality (adjusted HR, 2.10; 95% CI, 1.39-3.16 versus absence of late referral without history of volume overload) after adjusting for age, sex, diabetes, atherosclerotic disease, and laboratory values. CONCLUSIONS: Both late referral and history of volume overload were associated with increased risks of all-cause mortality. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN000007096). Registered 18 January 2012, retrospectively registered. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000008349 .

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.

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.

Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial.

Importance: Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels. Objective: To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis. Design, Setting, and Participants: Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015. Interventions: Treatment with 0.5 µg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481). Main Outcomes and Measures: The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death. Results: Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events. Conclusions and Relevance: Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these. Trial Registration: UMIN-CTR Identifier: UMIN000001194.

Physical function at the time of dialysis initiation is associated with subsequent mortality.

BACKGROUND: In dialysis patients, physical function is associated with mortality. However, the association between physical function at the time of dialysis initiation and subsequent mortality remains unknown. METHODS: A total of 1496 patients with chronic kidney disease who initiated dialysis at 17 centers participating in the Aichi Cohort Study of the Prognosis in Patients Newly Initiated into Dialysis, a multicenter prospective cohort study, were included. The patients were divided into the high (H)-, middle (M)-, and low (L)-score groups according to Barthel index (BI) at the time of dialysis initiation, and the all-cause, cardiovascular disease (CVD)-related, and infection-related mortality rates were compared. Moreover, factors affecting all-cause mortality were investigated. The effects of BI on mortality were assessed in the patients stratified by age, sex, and history of CVD or cerebral infarction. RESULTS: A log-rank test for the Kaplan-Meier survival curve showed significant differences between the three groups in all-cause, CVD-related, and infection-related mortality rates (p < 0.001). Cox proportional hazard regression analysis with the step-wise method showed a significantly higher risk of all-cause mortality in the M and L groups than in the H group (M group: HR 1.612, 95 % CI 1.075-2.417; L group: HR 1.994, 95 % CI 1.468-2.709). Regardless of the age categories and the history of CVD, the risk of all-cause mortality was significantly higher in the L group than in the H group. CONCLUSION: Physical function assessed by BI at the time of dialysis initiation was found to be associated with subsequent mortality.

Relationship between mortality and speed of eGFR decline in the 3 months prior to dialysis initiation.

BACKGROUND: The timing for initiating dialysis in chronic kidney disease is often determined by the clinical symptoms and estimated glomerular filtration rate (eGFR). However, very few studies have examined how the speed of kidney function decline before initiating dialysis relates to mortality after dialysis initiation. Here, we report our examination of the relationship between the speed of eGFR decline in the 3 months prior to dialysis initiation and mortality. METHODS: The study included 1292 new dialysis patients who were registered in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis. The subjects were placed in 4 groups based on the speed of eGFR decline in the 3 months before initiating dialysis (eGFR at 3 months before initiation-eGFR at initiation) <2: ≥2, <4: ≥4, <6: ≥6 mL/min/1.73 m2. All-cause, cardiovascular, and infection-related mortality rates were compared using Kaplan-Meier curves. A multivariate analysis using the Cox proportional hazard model was used to extract the factors that contributed to all-cause mortality. RESULTS: The group with faster eGFR decline exhibited significantly more heart failure symptoms when dialysis was initiated. Rapid eGFR decline correlated with prognosis (log-rank test: all-cause mortality p < 0.001, cardiovascular mortality p < 0.001). The speed of eGFR decline was related to elevated all-cause mortality rates [eGFR decline 10 mL/min/1.73 m2, HR (95 % CI) = 1.53 (1.12-2.08)]. CONCLUSIONS: This study showed that patients with rapid eGFR decline in the 3 months before initiating dialysis more often presented with heart failure symptoms when dialysis was initiated and had poorer survival prognoses.