Publications by authors named "Hideki Hirakata"

148 Publications

Routinely measured cardiac troponin I and N-terminal pro-B-type natriuretic peptide as predictors of mortality in haemodialysis patients.

ESC Heart Fail 2022 Jan 13. Epub 2022 Jan 13.

Fukuoka Renal Clinic, Fukuoka, Japan.

Aims: Cardiac troponin (cTn) and B-type natriuretic peptide (BNP) are elevated in haemodialysis (HD) patients, and this elevation is associated with HD-induced myocardial stunning/myocardial strain. However, studies using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS) have shown that these cardiac biomarkers are measured in <2% of HD patients in real-world practice. This study aimed to examine whether routinely measured N-terminal pro-BNP (NT-proBNP) and cTnI (contemporary assay) are more appropriate than clinical models for reclassifying the risk of HD patients who have the highest risk of death.

Methods And Results: Pre-dialysis levels of cTnI and NT-proBNP at study enrolment were measured in 1152 HD patients (Japan DOPPS Phase 5). The patients were prospectively followed for 3 years. Cox regression was used to test the associations of cardiac biomarkers with all-cause mortality, adjusting for potential confounders. Subgroup analyses were performed to assess potential effect modification of clinical characteristics, such as age, systolic blood pressure, HD vintage, diabetes mellitus, coronary artery disease, and a history of congestive heart failure. At baseline, 337 (29%) patients had elevated cTnI (99th percentile of a healthy population: >0.04 ng/mL) with a median (inter-quartile range) level of 0.020 (0.005-0.041) ng/mL, and 1140 (99%) patients had elevated NT-proBNP (cut-off for heart failure: >125 pg/mL) with a median level of 3658 (1689-9356) pg/mL. There were 167 deaths during a median follow-up of 2.8 (2.2-2.8) years. Higher levels of both cardiac biomarkers were incrementally associated with mortality after adjustment for potential confounders. Even after adjustment for alternative cardiac biomarkers, the overall P value for the association was <0.01 for both biomarkers. However, the prognostic significance of NT-proBNP was moderately diminished when cTnI was added to the model. The hazard ratios of mortality for cTnI > 0.04 ng/mL (vs. cTnI < 0.006 ng/mL) and NT-proBNP > 8000 pg/mL (vs. NT-proBNP < 2000 pg/mL) were 2.56 (95% confidence interval: 1.37-4.81) and 1.90 (95% confidence interval: 0.95-3.79), respectively. Subgroup analyses showed that the associations of both cardiac biomarkers with mortality were generally consistent between stratified groups.

Conclusions: Routinely measured NT-proBNP and cTnI levels are strongly associated with mortality among prevalent HD patients. These associations remain robust, even after adjustment for alternative biomarkers, suggesting that cTnI and NT-proBNP have identical prognostic significance and may reflect different pathological aspects of cardiac abnormalities.
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http://dx.doi.org/10.1002/ehf2.13784DOI Listing
January 2022

A Phase 3 Study of Enarodustat (JTZ-951) in Japanese Hemodialysis Patients for Treatment of Anemia in Chronic Kidney Disease: SYMPHONY HD Study.

Kidney Dis (Basel) 2021 Nov 5;7(6):494-502. Epub 2021 Jul 5.

Fukuoka Renal Clinic, Fukuoka, Japan.

Introduction: Enarodustat (JTZ-951) is a new oral hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). We conducted a phase 3 study to compare the efficacy and safety of enarodustat with darbepoetin alfa (DA) in Japanese anemic patients with CKD receiving maintenance hemodialysis.

Methods: Subjects receiving maintenance hemodialysis were randomly assigned at a 1:1 ratio to receive oral enarodustat once daily or intravenous DA every week for 24 weeks with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within a target range (≥10.0 to <12.0 g/dL). The primary efficacy endpoint was difference in mean Hb level between arms during the evaluation period defined as weeks 20-24 (noninferiority margin: -1.0 g/dL). Intravenous iron preparations were prohibited during the screening period and during weeks 0-4.

Results: The mean Hb level of each arm during the evaluation period was 10.73 g/dL (95% confidence interval [CI]: 10.56, 10.91) in the enarodustat arm and 10.85 g/dL (95% CI: 10.72, 10.98) in the DA arm. The difference in the mean Hb level between arms was -0.12 g/dL (95% CI: -0.33, 0.10), confirming the noninferiority of enarodustat to DA. The mean Hb level of each arm was maintained within the target range during the treatment period. Increased total iron-binding capacity and serum iron and decreased hepcidin were observed through week 4 in the enarodustat arm albeit after switching from erythropoiesis-stimulating agents. No apparent safety concerns of enarodustat were observed compared with DA.

Discussion/conclusion: Enarodustat was noninferior to DA for the treatment of anemia in CKD patients receiving maintenance hemodialysis and was generally well tolerated over 24 weeks.
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http://dx.doi.org/10.1159/000517053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613566PMC
November 2021

Association of fibroblast growth factor 23 and α-klotho in hemodialysis patients during administration of ferric citrate hydrate: post hoc analysis of ASTRIO study.

BMC Nephrol 2021 Nov 10;22(1):374. Epub 2021 Nov 10.

Fukuoka Renal Clinic, Fukuoka, Japan.

Background: Fibroblast growth factor-23 (FGF23) and α-klotho are associated with anemia in patients with chronic kidney disease. In this post hoc analysis of the ASTRIO study (UMIN000019176), we investigated the relationship between FGF23 and α-klotho during treatment with an iron-based phosphate binder, ferric citrate hydrate (FC), compared with non-iron-based phosphate binders in hemodialysis (HD) patients. We examined the effect of iron absorption by FC on the relationship between FGF23 and α-klotho. There have been few clinical studies evaluating these biomarkers simultaneously in HD patients.

Methods: The ASTRIO study was a 24-week, randomized, open-label, multicenter trial. HD patients taking non-iron-based phosphate binder(s) were randomized at a 1:1 ratio to continue other binder(s) (control group) or switch to FC (FC group). Serum phosphate (P) and hemoglobin (Hb) were maintained within 3.5-6.0 mg/dL and 10-12 g/dL, respectively. Plasma levels of intact FGF23 (i-FGF23), C-terminal FGF23 (c-FGF23), and α-klotho were measured, as were iron-related parameters. Association analyses of FGF23 and α-klotho were conducted.

Results: Patients were randomized to FC (n = 48) and control (n = 45) groups. Serum ferritin significantly increased from baseline to end-of-treatment (EOT) in the FC group, compared with the control group (adjusted mean difference [95% confidence interval]: 79.5 [44.7, 114.4] ng/mL; p <  0.001). The mean change from baseline to EOT in c-FGF23 was significantly different between the FC and control groups (mean ± standard deviation (SD): - 0.2 ± 0.8 log pg/mL vs. 0.2 ± 0.8 log pg/mL, respectively; p = 0.04). The mean change from baseline to EOT in i-FGF23 and α-klotho were not significantly different between the FC and control groups (mean ± SD: - 0.1 ± 0.8 log pg/mL vs. 0.1 ± 0.9 log pg/mL; p = 0.33, and 2.0 ± 91.5 pg/mL vs. - 8.9 ± 145.3; p = 0.58, respectively). However, both forms of FGF23 and α-klotho were not significantly associated with each other in both groups.

Conclusions: Iron absorbed via FC administration in HD patients did not influence the correlation relationship between plasma levels of FGF23 and α-klotho under the condition of serum P and Hb were maintained.

Trial Registration: ASTRIO study ( UMIN000019176 , registered at UMIN Clinical Trials Registry on October 1, 2015).
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http://dx.doi.org/10.1186/s12882-021-02575-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582217PMC
November 2021

Association of dialysis-related amyloidosis with lower quality of life in patients undergoing hemodialysis for more than 10 years: The Kyushu Dialysis-Related Amyloidosis Study.

PLoS One 2021 24;16(8):e0256421. Epub 2021 Aug 24.

Fukuoka Renal Clinic, Fukuoka, Japan.

Background: Dialysis-related amyloidosis (DRA) commonly develops in patients undergoing long-term dialysis and can lead to a decline in activities of daily living and quality of life (QOL), mainly owing to orthopedic complications.

Methods: First, we determined utility scores of the EuroQol 5-Dimensions 3-Levels (EQ-5D-3L) questionnaire in 1,323 patients with DRA who had undergone dialysis for more than 10 years and compared the score between those with and without DRA. Second, a 2-year follow-up was also performed, in which patients were divided into three groups: those complicated by DRA from the beginning, those with newly developed DRA within the 2-year period, and those not complicated by DRA throughout the survey period; changes in the EQ-5D-3L utility score were compared. In the group already complicated by DRA at the survey baseline, changes in the EQ-5D-3L utility score were compared according to the dialysis treatment method.

Results: A total of 1,314 and 931 patients were included in the first and second studies, respectively. EQ-5D-3L utility scores among patients diagnosed with DRA were significantly lower than scores in those not diagnosed with DRA. The reduction in the EQ-5D-3L utility score over the 2-year follow-up was significantly greater in patients newly complicated by DRA during the follow-up period after enrollment but not in those complicated by DRA from the beginning, as compared with patients not complicated by DRA throughout the survey period. The reduction in utility score tended to be lower in patients routinely treated with a β2-microglobulin adsorption column than in untreated patients with DRA.

Conclusion: Complication by DRA in patients undergoing long-term hemodialysis was significantly associated with a decline in QOL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256421PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384206PMC
December 2021

Two long-term phase 3 studies of enarodustat (JTZ-951) in Japanese anemic patients with chronic kidney disease not on dialysis or on maintenance hemodialysis: SYMPHONY ND-Long and HD-Long studies.

Ther Apher Dial 2021 Aug 13. Epub 2021 Aug 13.

Fukuoka Renal Clinic, Fukuoka, Japan.

Enarodustat (JTZ-951) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed for treating anemia in chronic kidney disease. Two open-label, uncontrolled phase 3 studies evaluated the 52-week safety and efficacy of enarodustat in Japanese anemic patients with chronic kidney disease not on dialysis (n = 132) [SYMPHONY ND-Long study] or on maintenance hemodialysis (n = 136) [SYMPHONY HD-Long study]. The most frequent adverse events were viral upper respiratory tract infection (25.8%) followed by chronic kidney disease (8.3%) in the SYMPHONY ND-Long study, and viral upper respiratory tract infection (49.3%) followed by contusion (16.9%) and diarrhea (16.9%) in the SYMPHONY HD-Long study. The incidence of any adverse events did not increase over time. Mean hemoglobin levels and 95% confidence intervals were maintained within the target range (10.0-12.0 g/dl) over 52 weeks in both studies. The long-term safety and efficacy of enarodustat were confirmed in Japanese anemic patients with chronic kidney disease.
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http://dx.doi.org/10.1111/1744-9987.13724DOI Listing
August 2021

A Phase 3 Study of Enarodustat in Anemic Patients with CKD not Requiring Dialysis: The SYMPHONY ND Study.

Kidney Int Rep 2021 Jul 12;6(7):1840-1849. Epub 2021 May 12.

Fukuoka Renal Clinic, Fukuoka, Japan.

Introduction: Enarodustat (JTZ-951) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that might be a new therapeutic approach for managing anemia in patients with chronic kidney disease (CKD). We evaluated the efficacy (noninferiority to darbepoetin alfa [DA]) and safety of enarodustat in Japanese anemic patients with CKD not requiring dialysis.

Methods: Erythropoiesis-stimulating agent (ESA)-naïve patients and ESA-treated patients were randomized at a 1:1 ratio to receive enarodustat orally once daily or DA subcutaneously every 2 or 4 weeks for 24 weeks, respectively. Subjects in each arm had dose adjustments every 4 weeks to maintain their hemoglobin (Hb) level within the target range (10 to 12 g/dl). The primary endpoint was the difference in the mean Hb level between arms during the evaluation period defined as weeks 20 to 24 (noninferiority margin: -0.75 g/dl).

Results: The mean Hb level during the evaluation period in the enarodustat arm was 10.96 g/dl (95% confidence interval [CI]: 10.84 to 11.07 g/dl) with a difference of 0.09 g/dl (95% CI: -0.07 to 0.26 g/dl) between arms, establishing its noninferiority to DA. Nearly 90% of subjects in both arms maintained a mean Hb level within the target range. Compared with DA, enarodustat was associated with decreased hepcidin and ferritin, and increased total iron-binding capacity. There were no apparent differences in the incidence of adverse events between arms (65.4% [enarodustat], 82.6% [DA]).

Conclusions: The efficacy of enarodustat was comparable to DA in anemic patients with CKD not requiring dialysis. No new safety concerns were identified compared with DA.
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http://dx.doi.org/10.1016/j.ekir.2021.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258589PMC
July 2021

Association of blood pressure after peritoneal dialysis initiation with the decline rate of residual kidney function in newly-initiated peritoneal dialysis patients.

PLoS One 2021 8;16(7):e0254169. Epub 2021 Jul 8.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Lower blood pressure (BP) levels are linked to a slower decline of kidney function in patients with chronic kidney disease (CKD) without kidney replacement therapy. However, there are limited data on this relation in peritoneal dialysis (PD) patients. Here we evaluated the association of BP levels with the decline of residual kidney function (RKF) in a retrospective cohort study.

Methods: We enrolled 228 patients whose PD was initiated between 1998 and 2014. RKF was measured as the average of creatinine and urea clearance in 24-hr urine collections. We calculated the annual decline rate of RKF by determining the regression line for individual patients. RKF is thought to decline exponentially, and thus we also calculated the annual decline rate of logarithmic scale of RKF (log RKF). We categorized the patients' BP levels at 3 months after PD initiation (BP3M) into four groups (Optimal, Normal & High normal, Grade 1 hypertension, Grade 2 & 3 hypertension) according to the 2018 European Society of Cardiology and European Society of Hypertension Guidelines for the management of arterial hypertension.

Results: The unadjusted, age- and sex-adjusted, and multivariable-adjusted decline rate of RKF and log RKF decreased significantly with higher BP3M levels (P for trend <0.01). Compared to those of the Optimal group, the multivariable-adjusted odds ratios (95% confidence interval) for the faster side of the median decline rate of RKF and log RKF were 4.04 (1.24-13.2) and 5.50 (1.58-19.2) in the Grade 2 and 3 hypertension group, respectively (p<0.05).

Conclusions: Higher BP levels after PD initiation are associated with a faster decline in RKF among PD patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254169PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266121PMC
November 2021

Effect of Treating Hyperphosphatemia With Lanthanum Carbonate vs Calcium Carbonate on Cardiovascular Events in Patients With Chronic Kidney Disease Undergoing Hemodialysis: The LANDMARK Randomized Clinical Trial.

JAMA 2021 05;325(19):1946-1954

Division of Nephrology, Department of Medicine, Showa University School of Medicine, Shinagawa, Tokyo, Japan.

Importance: Among patients with hyperphosphatemia undergoing dialysis, it is unclear whether non-calcium-based phosphate binders are more effective than calcium-based binders for reducing cardiovascular events.

Objective: To determine whether lanthanum carbonate reduces cardiovascular events compared with calcium carbonate in patients with hyperphosphatemia at risk of vascular calcification undergoing hemodialysis.

Design, Setting, And Participants: Open-label, randomized, parallel-group clinical trial with blinded end point adjudication performed in 2374 patients with chronic kidney disease from 273 hemodialysis facilities in Japan. Eligible patients had hyperphosphatemia and 1 or more risk factors for vascular calcification (ie, ≥65 years, postmenopausal, diabetes). Enrollment occurred from November 2011 to July 2014; follow-up ended June 2018.

Interventions: Patients were randomized to receive either lanthanum carbonate (n = 1154) or calcium carbonate (n = 1155) and titrated to achieve serum phosphate levels of between 3.5 mg/dL and 6.0 mg/dL.

Main Outcomes And Measures: The primary outcome was a composite cardiovascular event (cardiovascular death, nonfatal myocardial infarction or stroke, unstable angina, transient ischemic attack, or hospitalization for heart failure or ventricular arrhythmia). Secondary outcomes included overall survival, secondary hyperparathyroidism-free survival, hip fracture-free survival, and adverse events.

Results: Among 2309 randomized patients (median age, 69 years; 40.5% women), 1851 (80.2%) completed the trial. After a median follow-up of 3.16 years, cardiovascular events occurred in 147 of 1063 patients in the lanthanum calcium group and 134 of 1072 patients in the calcium carbonate group (incidence rate, 4.80 vs 4.30 per 100 person-years; difference 0.50 per 100 person-years [95% CI, -0.57 to 1.56]; hazard ratio [HR], 1.11 [95%, CI, 0.88 to 1.41], P = .37). There were no significant differences in all-cause death (difference, 0.43 per 100 person-years [95% CI, -0.63 to 1.49]; HR, 1.10 [95% CI, 0.88 to 1.37]; P = .42) or hip fracture (difference, 0.10 per 100 person-years [95% CI, -0.26 to 0.47]; HR, 1.21 [95% CI, 0.62 to 2.35]; P = .58). The lanthanum carbonate group had an increased risk of cardiovascular death (difference, 0.61 per 100 person-years [95% CI, 0.02 to 1.21]; HR, 1.51 [95% CI, 1.01 to 2.27]; P = .045) and secondary hyperparathyroidism (difference, 1.34 [95% CI, 0.49 to 2.19]; HR, 1.62 [95% CI, 1.19 to 2.20]; P = .002). Adverse events occurred in 282 (25.7%) in the lanthanum carbonate group and 259 (23.4%) in the calcium carbonate groups.

Conclusions And Relevance: Among patients undergoing hemodialysis with hyperphosphatemia and at least 1 vascular calcification risk factor, treatment of hyperphosphatemia with lanthanum carbonate compared with calcium carbonate did not result in a significant difference in composite cardiovascular events. However, the event rate was low, and the findings may not apply to patients at higher risk.

Trial Registration: ClinicalTrials.gov Identifier: NCT01578200; UMIN Clinical Trial Registry Identifier: UMIN000006815.
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http://dx.doi.org/10.1001/jama.2021.4807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132143PMC
May 2021

The combination of malnutrition-inflammation and functional status limitations is associated with mortality in hemodialysis patients.

Sci Rep 2021 01 15;11(1):1582. Epub 2021 Jan 15.

Arbor Research Collaborative for Health, Ann Arbor, MI, USA.

The identification of malnutrition-inflammation-complex (MIC) and functional status (FS) is key to improving patient experience on hemodialysis (HD). We investigate the association of MIC and FS combinations with mortality in HD patients. We analyzed data from 5630 HD patients from 9 countries in DOPPS phases 4-5 (2009-2015) with a median follow-up of 23 [IQR 11, 31] months. MIC was defined as serum albumin < 3.8 g/dL and serum C-reactive protein > 3 mg/L in Japan and > 10 mg/L elsewhere. FS score was defined as the sum of scores from the Katz Index of Independence in Activities of Daily Living and the Lawton-Brody Instrumental Activities of Daily Living Scale. We investigated the association between combinations of MIC (+/-) and FS (low [< 11]/high [≥ 11]) with death. Compared to the reference group (MIC-/high FS), the adjusted hazard ratios [HR (95% CI)] for all-cause mortality were 1.82 (1.49, 2.21) for MIC-/low FS, 1.57 (1.30, 1.89) for MIC+/high FS, and 3.44 (2.80, 4.23) for MIC+/low FS groups. Similar associations were observed with CVD-related and infection-related mortality. The combination of MIC and low FS is a strong predictor of mortality in HD patients. Identification of MIC and poor FS may direct interventions to lessen adverse clinical outcomes in the HD setting.
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http://dx.doi.org/10.1038/s41598-020-80716-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811014PMC
January 2021

Renal prognoses by different target hemoglobin levels achieved by epoetin beta pegol dosing to chronic kidney disease patients with hyporesponsive anemia to erythropoiesis-stimulating agent: a multicenter open-label randomized controlled study.

Clin Exp Nephrol 2021 May 7;25(5):456-466. Epub 2021 Jan 7.

Fukuoka Renal Clinic, Fukuoka, Japan.

Background: There is no evidence regarding appropriate target hemoglobin levels in chronic kidney disease (CKD) patients with an erythropoiesis-stimulating agent (ESA)-hyporesponsiveness. Therefore, we conducted a randomized controlled study in non-dialysis dependent CKD (NDD-CKD) patients with ESA-hyporesponsiveness, comparing results of intensive versus conservative treatment to maintain hemoglobin levels.

Methods: This was a multicenter, open-label, randomized, parallel-group study conducted at 89 institutions. Among NDD-CKD patients, those with ESA-hyporesponsive renal anemia were randomly assigned to an intensive treatment group, to which epoetin beta pegol was administered with target hemoglobin level of 11 g/dL or higher, or conservative treatment group, in which the hemoglobin levels at enrollment (within ± 1 g/dL) were maintained. The primary endpoint was the time to the first kidney composite event defined as (1) transition to renal replacement therapy (dialysis or renal transplantation); (2) reduction of estimated glomerular filtration rate (eGFR) to less than 6.0 mL/min/1.73 m; or (3) reduction of eGFR by 30% or more. Secondary endpoints were kidney function (change rate in eGFR), cardiovascular (CV) events, and safety.

Results: Between August 2012 and December 2015, 385 patients were registered, and 362 patients who met the eligibility criteria were enrolled. There was no significant difference in kidney survival or in CV events between the two groups. However, the incidences of the 3 types of kidney composite events tended to differ.

Conclusions: In NDD-CKD patients with ESA-hyporesponsive renal anemia, the aggressive administration of ESA did not clearly extend kidney survival or result in a significant difference in the incidence of CV events.
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http://dx.doi.org/10.1007/s10157-020-02005-4DOI Listing
May 2021

Initial responsiveness to darbepoetin alfa and its contributing factors in non-dialysis chronic kidney disease patients in Japan.

Clin Exp Nephrol 2021 Feb 19;25(2):110-119. Epub 2020 Sep 19.

Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 757 Ichibancho Asahimachidori Chuo-ku, Niigata, 951-8510, Japan.

Background: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease (CKD). This study aimed to investigate the initial responsiveness to darbepoetin alfa (DA) and its contributing factors using the data from the BRIGHTEN.

Methods: Of 1980 patients enrolled at 168 facilities, 1695 were included in this analysis [285 patients were excluded mainly due to lack of hemoglobin (Hb) values]. The initial ESA response index (iEResI) was defined as a ratio of Hb changes over 12 weeks after DA administration per weight-adjusted total DA dose and contributing factors to iEResI were analyzed.

Results: The mean age was 70 ± 12 years (male 58.8%; diabetic nephropathy 27.6%). The median creatinine and mean Hb levels at DA initiation were 2.62 mg/dL and 9.8 g/dL, respectively. The most frequent number of DA administration during 12 weeks was 3 times (41.1%), followed by 4 (15.6%) times with a wide distribution of the total DA dose (15-900 μg). Remarkably, 225 patients (13.3%) did not respond to DA. Multivariate analysis showed that male gender, hypoglycemic agent use, iron supplementation, high eGFR, low Hb, low CRP, low NT-proBNP, and low urinary protein-creatinine ratio were independently associated with better initial response to DA (P =  < 0.0001, 0.0108, < 0.0001, 0.0476, < 0.0001, 0.0004, 0.0435, and 0.0009, respectively).

Conclusions: Non-responder to DA accounted for 13.3% of patients with non-dialysis CKD. Iron supplementation, low CRP, low NT-proBNP, and less proteinuria were predictive and modifiable factors associated with better initial response to DA.
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http://dx.doi.org/10.1007/s10157-020-01969-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880978PMC
February 2021

Short- and Long-term Effects of Dialysate Calcium Concentrations on Mineral and Bone Metabolism in Hemodialysis Patients: The K4 Study.

Kidney Med 2019 Sep-Oct;1(5):296-306. Epub 2019 Sep 11.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Rationale & Objective: The short- and long-term impact of conversion of dialysate calcium concentration from either 2.5 or 3.0 mEq/L to 2.75 mEq/L on mineral and bone metabolism remains unknown in hemodialysis patients.

Study Design: Nonrandomized intervention study.

Setting & Population: 12 hemodialysis patients treated at baseline with a 2.5-mEq/L dialysate calcium concentration and another 12 hemodialysis patients treated with a 3.0-mEq/L dialysate calcium concentration.

Intervention: Use of 2.75-mEq/L dialysate calcium concentration.

Outcomes: Changes in intradialytic calcium and phosphate clearance and changes in predialysis and intradialytic serum and ionized mineral and biochemical parameters over the 24 weeks following dialysate calcium conversion.

Results: Conversion of dialysate calcium concentration from 2.5 to 2.75 mEq/L increased intradialytic calcium loading and serum total and ionized calcium levels, whereas conversion of dialysate calcium from 3.0 to 2.75 mEq/L decreased intradialytic calcium loading and serum total and ionized calcium levels. Dialysate calcium concentration conversion did not affect intradialytic serum parathyroid hormone level, intradialytic phosphate elimination, or predialysis serum calcium, phosphate, parathyroid hormone, and fibroblast growth factor 23 levels. Intradialytic calcium influx was determined by dialysate calcium concentration and predialysis serum calcium levels, whereas intradialytic phosphate elimination was determined by predialysis serum phosphate levels.

Limitations: Small sample size and no control groups treated with 2.5- and 3.0-mEq/L dialysate calcium concentrations during the 24 weeks of the observation period.

Conclusions: Conversion of dialysate calcium concentration from either 3.0 or 2.5 to 2.75 mEq/L results in expected changes in calcium loading based on predialysis calcium concentration. The dialysate calcium concentration should be personalized based on clinical factors.

Funding: None.

Trial Registration: University Hospital Medical Information Network, www.umin.ac.jp/english/, R000040105, UMIN000035184.
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http://dx.doi.org/10.1016/j.xkme.2019.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380384PMC
September 2019

Late renal recovery after treatment over 1 year post-onset in an atypical hemolytic uremic syndrome: a case report.

BMC Nephrol 2020 06 22;21(1):236. Epub 2020 Jun 22.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease that leads to end-stage kidney disease if only a poor response to plasma exchanges (PEs) or eculizumab therapy is achieved.

Case Presentation: A 58-year-old Japanese man presented with thrombocytopenia, anemia, and kidney failure requiring dialysis without any underlying disease. A kidney biopsy revealed marked mesangiolysis in all glomeruli, compatible with thrombotic microangiopathy (TMA). Based on the positive anti- factor H antibody and negative result for secondary TMA, we diagnosed him as aHUS. Despite eculizumab administration after eight sessions of PE, neither platelet normalization nor kidney recovery was achieved. Eight months later, we discontinued eculizumab therapy due to anaphylactic reaction. At 15 months after the onset of TMA, his platelet count increased gradually from 40 to 150 × 10/μL with a decreased serum creatinine level and increased urine output, eventually allowing the withdrawal of dialysis therapy. A second kidney biopsy showed mesangial widening compatible with the healing of TMA.

Conclusions: This case indicates that aHUS with PEs and eculizumab therapy has the potential for renal recovery even if over 1 year has passed.
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http://dx.doi.org/10.1186/s12882-020-01897-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310110PMC
June 2020

Darbepoetin Alfa in Patients with Advanced CKD without Diabetes: Randomized, Controlled Trial.

Clin J Am Soc Nephrol 2020 05 3;15(5):608-615. Epub 2020 Apr 3.

Division of Nephrology, Showa University School of Medicine, Tokyo, Japan.

Background And Objectives: Large, randomized, controlled trials targeting higher hemoglobin level with erythropoiesis-stimulating agents for Western patients with CKD showed harm. However, the effect of anemia correction using erythropoiesis-stimulating agents may differ between CKD subpopulations. The Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease study, a multicenter, randomized, open-label, parallel-group study, aimed to examine the effect of targeting hemoglobin levels of 11-13 g/dl using darbepoetin alfa with reference to a low-hemoglobin target of 9-11 g/dl on kidney outcome in patients with advanced CKD without diabetes in Japan.

Design, Setting, Participants, & Measurements: We enrolled 491 patients with CKD without diabetes, and an eGFR of 8-20 ml/min per 1.73 m. Of these 491 patients, 239 and 240 were ultimately assigned to the high- and low-hemoglobin groups, respectively (12 patients were excluded). The primary outcome was a kidney composite end point (starting maintenance dialysis, kidney transplantation, eGFR≤6 ml/min per 1.73 m, and 50% reduction in eGFR).

Results: Mean hemoglobin levels were 11.2±1.1 and 10.0±0.9 g/dl in the high- and low-hemoglobin groups, respectively, during the mean study period of 73.5±29.7 weeks. The kidney composite end point occurred in 105 (44%) and 116 (48%) patients in the high- and low-hemoglobin groups, respectively (log-rank test; =0.32). The adjusted Cox proportional hazards model showed that the hazard ratio for the high- versus low-hemoglobin group was 0.78 (95% confidence interval, 0.60 to 1.03; =0.08). Cardiovascular events occurred in 19 (8%) and 16 (7%) patients in each group, respectively, with no significant between-group difference (log-rank test; =0.66).

Conclusions: Targeting a higher hemoglobin level (11-13 g/dl) with darbepoetin alfa did not improve kidney outcome compared with targeting a lower hemoglobin level (9-11 g/dl) in patients with advanced CKD without diabetes.

Clinical Trial Registry Name And Registration Number: Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease (PREDICT), NCT01581073.
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http://dx.doi.org/10.2215/CJN.08900719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269223PMC
May 2020

Postdialysis blood pressure is a better predictor of mortality than predialysis blood pressure in Japanese hemodialysis patients: the Japan Dialysis Outcomes and Practice Patterns Study.

Hypertens Res 2020 08 19;43(8):791-797. Epub 2020 Mar 19.

Fukuoka Renal Clinic, Fukuoka, Japan.

Blood pressure (BP) is reportedly a predictor of mortality in hemodialysis (HD) patients; however, it is unclear whether pre- or postdialysis BP has greater predictive power. To evaluate the association of pre- and postdialysis BP with patient survival in Japanese HD patients, we enrolled the entire phase 3 and 4 Japan Dialysis Outcomes and Practice Patterns Study populations. Among 3176 patients, 486 were excluded because of missing data. The remaining 2690 patients were divided into five groups according to pre- or postdialysis systolic BP (SBP): <100, 100-119, 120-139, 140-159, and ≥160 mmHg; diastolic BP (DBP): <60, 60-79, 80-89, 90-99, and ≥100 mmHg; or pulse pressure (PP): <50, 50-59, 60-69, 70-79, and ≥80 mmHg. The hazard ratios for all-cause and cardiovascular mortalities were estimated according to pre- and postdialysis SBP, DBP, and PP using a Cox proportional hazards model. During the follow-up period, 495 and 193 subjects died because of any cause and cardiovascular disease (CVD), respectively. In the multivariable-adjusted Cox proportional hazards model, U-shaped associations of postdialysis SBP and PP with mortality rates were observed, but no significant associations were observed with predialysis SBP or PP. A stratified analysis showed significant interactions between history of CVD and postdialysis SBP with all-cause and cardiovascular mortality. Compared with predialysis values, postdialysis SBP and PP are better predictors of all-cause and cardiovascular mortality, showing U-shaped associations with these outcomes in Japanese HD patients.
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http://dx.doi.org/10.1038/s41440-020-0425-1DOI Listing
August 2020

Randomised clinical trial of ferric citrate hydrate on anaemia management in haemodialysis patients with hyperphosphataemia: ASTRIO study.

Sci Rep 2019 06 20;9(1):8877. Epub 2019 Jun 20.

Fukuoka Renal Clinic, Fukuoka, Japan.

Ferric citrate hydrate (FC) is an iron-based phosphate binder approved for hyperphosphataemia in patients with chronic kidney disease. We conducted a randomised controlled trial to evaluate the effects of FC on anaemia management in haemodialysis patients with hyperphosphataemia. We 1:1 randomised 93 patients who were undergoing haemodialysis and being treated with non-iron-based phosphate binders and erythropoiesis-stimulating agents (ESA) to receive 24 weeks of FC or to continue their non-iron-based phosphate binders (control) in a multicentre, open-label, parallel-design. Phosphate level was controlled within target range (3.5-6.0 mg/dL). The primary endpoint was change in ESA dose from baseline to end of treatment. Secondary endpoints were changes in red blood cell, iron and mineral, and bone-related parameters. Compared with control, FC reduced ESA dose [mean change (SD), -1211.8 (3609.5) versus +1195 (6662.8) IU/week; P = 0.03] without significant differences in haemoglobin. FC decreased red blood cell distribution width (RDW) compared with control. While there were no changes in serum phosphate, FC reduced C-terminal fibroblast growth factor (FGF) 23 compared with control. The incidence of adverse events did not differ significantly between groups. Despite unchanged phosphate and haemoglobin levels, FC reduced ESA dose, RDW, and C-terminal FGF23 compared with control.
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http://dx.doi.org/10.1038/s41598-019-45335-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586649PMC
June 2019

Enarodustat, Conversion and Maintenance Therapy for Anemia in Hemodialysis Patients: A Randomized, Placebo-Controlled Phase 2b Trial Followed by Long-Term Trial.

Nephron 2019 22;143(2):77-85. Epub 2019 May 22.

Fukuoka Renal Clinic, Fukuoka, Japan.

Background: Enarodustat (JTZ-951) is an orally available hypoxia-inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin levels in the treatment of anemia associated with chronic kidney disease (CKD).

Objective: A phase 2b study of enarodustat to assess the hemoglobin (Hb) response, safety, and maintenance dosage was conducted in Japanese anemic patients with hemodialysis-dependent CKD.

Methods: Subjects receiving a stable dose of an erythropoiesis-stimulating agent were randomized to receive once-daily enarodustat at a dose of 2, 4, or 6 mg or placebo in a double-blind manner for 6 weeks (Period 1) followed by 24-week open treatment with enarodustat, adjusted in the range of 2-8 mg to maintain Hb within a target range (10.0-12.0 g/dL; Period 2).

Results: Change in Hb from baseline increased with enarodustat dose in Period 1. In Period 2, the proportion of subjects who maintained their Hb level within the target range at the end of treatment was 65.1%. To maintain Hb levels within the target range over the course of Period 2, approximately 80% of subjects required 2 dose adjustments or fewer. Enarodustat decreased hepcidin and ferritin levels, increased total iron-binding capacity, and was generally well tolerated.

Conclusions: Enarodustat corrected and maintained Hb levels in anemic patients with hemodialysis-dependent CKD. Phase 3 studies of enarodustat are currently ongoing.
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http://dx.doi.org/10.1159/000500487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878752PMC
May 2020

A Placebo-Controlled, Randomized Trial of Enarodustat in Patients with Chronic Kidney Disease Followed by Long-Term Trial.

Am J Nephrol 2019 30;49(2):165-174. Epub 2019 Jan 30.

Fukuoka Renal Clinic, Fukuoka, Japan.

Background: Enarodustat (JTZ-951) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that mimics adaptive responses to hypoxic conditions and may provide a new therapeutic approach for managing anemia in patients with chronic kidney disease (CKD). We evaluated the efficacy, safety, and maintenance dose of enarodustat in anemic patients with CKD not on dialysis.

Methods: Erythropoiesis-stimulating agent (ESA) naïve patients (correction group) and patients on a stable dose of ESA (conversion group) were randomized to receive 2, 4, or 6 mg of enarodustat or placebo once daily for 6 weeks in a double-blind manner (Period 1) followed by 24 weeks of open enarodustat treatment to maintain their hemoglobin (Hb) levels within a target range of 10.0-12.0 g/dL in reference to a dose adjustment algorithm (Period 2).

Results: In the correction group, Hb level increase rate per week increased in a dose-response manner. The proportion of subjects in the conversion group who maintained Hb levels within ± 1.0 g/dL of baseline did not differ between each enarodustat arm and placebo arm during Period 1. Over 70% of subjects in both groups maintained Hb levels within the target range at the end of treatment in Period 2. The mean prescribed doses were 3.58 and 3.74 mg/day in the correction group and the conversion group, respectively. Enarodustat was associated with decreases in hepcidin and ferritin and increased total iron-binding capacity and was generally well tolerated.

Conclusions: Enarodustat corrects and maintains Hb levels in anemic patients with CKD not on dialysis.
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http://dx.doi.org/10.1159/000496929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481254PMC
April 2020

Prognostic value of pre-dialysis blood pressure and risk threshold on clinical outcomes in hemodialysis patients: The Q-Cohort Study.

Medicine (Baltimore) 2018 Dec;97(51):e13485

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University.

The influence of pre-dialysis blood pressure (BP) on the prognosis of hemodialysis (HD) patients is still inconclusive.A total of 3436 HD patients were prospectively followed up for 4 years. The patients were divided into quintiles of pre-dialysis systolic BP (SBP) and diastolic BP (DBP) levels [mm Hg]: Quintile 1 (Q1), SBP <134, DBP <66; Q2, SBP 134 to 147, DBP 66 to 72; Q3, SBP 148 to 158, DBP 73 to 79; Q4, SBP 159 to 171, DBP 80 to 85; Q5, SBP ≥172, DBP ≥86. The association between the pre-dialysis BP and outcomes were examined using a Cox proportional hazards model.During a 4-year follow-up period, 564 (16.4%) patients died of any cause and 590 (17.2%) developed cardiovascular (CV) events. The lowest level of pre-dialysis SBP group (Q1) showed a significantly increased risk of all-cause mortality (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.40-2.39) and the highest group (Q5) significantly increased risk of CV events (HR 1.31, 95% CI 1.02-1.68) compared with the reference group (Q3), respectively. The highest level of pre-dialysis DBP group was significantly associated with increased risk for both all-cause mortality and CV events. Restricted cubic spline analysis for BP and outcomes suggested the optimal pre-dialysis BP value associated with the lowest risk of outcomes was SBP 152 mm Hg for all-cause mortality, SBP 143 mm Hg for CV events, and DBP 68 mm Hg for all-cause mortality.Our results suggested that pre-dialysis BP was independently associated with all-cause mortality and CV events among Japanese HD patients.
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http://dx.doi.org/10.1097/MD.0000000000013485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320176PMC
December 2018

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

JAMA 2018 12;320(22):2325-2334

Department of Kidney Disease, Kawashima Hospital, Tokushima, Japan.

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.
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http://dx.doi.org/10.1001/jama.2018.17749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583075PMC
December 2018

Dialysate Calcium Concentration below 3.0 mEq/L Is Not Associated with Improved Outcomes in the Japanese Dialysis Outcomes and Practice Patterns Study.

Nephron 2018 19;140(4):240-248. Epub 2018 Oct 19.

Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA.

Background: Abnormal chronic kidney disease-mineral and bone disorder (CKD-MBD) markers have been associated with adverse outcomes in hemodialysis (HD) patients. Dialysate calcium concentration (D-Ca) likely influences serum calcium and phosphorus levels. Optimal D-Ca level remains unclear. We hypothesized that higher D-Ca is associated with cardiovascular events and mortality among Japanese HD patients.

Methods: Enrollment data of chronic HD patients in the prospective observational study JDOPPS, phases 1-5 (1999-2015), provided exposures and covariates. All-cause mortality, non-arrhythmic cardiovascular events (NonAR-CVE), or their composites were analyzed by D-Ca, and divided into 2.5, 2.75, and 3.0 mEq/L. To minimize confounding by indication, analyses were restricted to facilities in which at least 90% of patients received the same D-Ca prescription. Association of D-Ca level with outcomes was evaluated in Cox models stratified by phase and accounting for facility clustering. Covariates describing patient demographics, comorbidities, laboratory values, CKD-MBD therapy, and facility attributes provided adjustment.

Results: Of 9,201 patients included, 25.0% had D-Ca of 2.5 mEq/L; 6.8% D-Ca 2.75; and 68.2% D-Ca 3.0. Median follow-up time was 2.03 years. D-Ca was not associated with all-cause mortality, with hazards ratios for 2.5 vs. 3.0 mEq/L of 0.90 and 95% CI (0.73-1.11), nor with other outcomes. One effect modification occurred, protective for lower D-Ca on NonAR-CVE in the absence of cardiovascular comorbidities (p = 0.032), although corresponding D-Ca effects were not significant after multiple comparisons adjustment (p = 0.261 [D-Ca 2.5] and 0.125 [D-Ca 2.75]).

Conclusion: Lowering D-Ca level below 3.0 mEq/L seems not to have a meaningful effect on patient outcomes.
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http://dx.doi.org/10.1159/000493470DOI Listing
October 2019

Use of phosphate-binders and risk of infection-related and all-cause mortality in patients undergoing hemodialysis: The Q-Cohort Study.

Sci Rep 2018 07 30;8(1):11387. Epub 2018 Jul 30.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

The use of phosphate (P)-binders allows hemodialysis patients to take in more protein and thus may maintain a good nutritional status. Protein-energy-malnutrition increases the risk of infection-related death. The association between use of P-binders and the relative risks of infection-related death remains unknown in hemodialysis patients. A total of 2926 hemodialysis patients registered to the Q-Cohort Study was followed up for 4-years. The association between use of P-binders and the risks for infection-related and all-cause mortality were estimated by Cox proportional hazards risk model with multiple adjustments by conventional and propensity-score based approaches. During the follow-up period, 106 patients and 492 patients died of infection and any cause, respectively. Cox proportional hazards models with multivariable adjustments including nutritional confounders showed that the incidence of infection-related death was significantly lower in patients with P-binders use compared with those without (hazard ratio [95% confidence interval] for infection-related mortality 0.63 [0.40-0.99]). The results remained significant even after applying four different propensity score-based analyses. Notably, use of P-binders was associated with a lower risk of all-cause mortality. Further studies including randomized controlled clinical trials and observational studies analyzed by an instrumental variable model will provide more robust evidences for the associations observed in our study.
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http://dx.doi.org/10.1038/s41598-018-29757-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065422PMC
July 2018

Study on Dialysis Session Length and Mortality in Maintenance Hemodialysis Patients: The Q-Cohort Study.

Nephron 2018 7;139(4):305-312. Epub 2018 Jun 7.

Department of Medicine and Clinical Science, Fukuoka, Japan.

Objectives: Hemodialysis (HD) time has been recognized as an important factor in dialysis adequacy. However, few studies have reported on associations between HD time and prognosis among maintenance HD patients. We present some findings from a prospective cohort study, the -Q-Cohort Study, which was set up to explore risk factors for mortality in Japanese HD patients. We hypothesized that HD ≥5 h was associated with a significant survival advantage compared with HD < 5 h. The present study examined association between HD time and mortality in Japanese HD patients.

Methods: The prospective multicenter Q-Cohort Study was conducted between December 2006 and December 2010, following 3,456 Japanese HD patients for 4 years. We examined the association between HD time and prognosis using Cox proportional hazards modeling. Propensity scores were calculated using logistic regression.

Results: During follow-up, 566 patients died from any cause. Patients with HD ≥5 h (n = 2,141) showed -significantly lower risk of all-cause death (hazards ratio = 0.82; 95% CI 0.68-0.99) than those with HD < 5 h (n = 1,315), after adjusting for confounding risk factors. This -association remained significant using a propensity score-based approach. After stratifying the analysis by patient age in 10-year increments, this finding remained -significant only in patients who were ≥80 years of age.

Conclusion: Our results suggest that HD ≥5 h has a more favorable effect on mortality than HD < 5 h.
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http://dx.doi.org/10.1159/000489680DOI Listing
September 2019

Oral Ferric Citrate Hydrate Associated With Less Oxidative Stress Than Intravenous Saccharated Ferric Oxide.

Kidney Int Rep 2018 Mar 3;3(2):364-373. Epub 2017 Nov 3.

Fukuoka Renal Clinic, Fukuoka, Japan.

Introduction: A recent study suggested that orally dosed ferric citrate hydrate (FC) corrects renal anemia in patients on hemodialysis (HD), suggesting biological differences in effects of iron supplementation using different routes of administration. To address this issue, the present study compared oral FC with i.v. saccharated ferric oxide (FO) in stable HD patients.

Methods: Participants comprised 6 patients administered 3 consecutive protocols in the first HD session of the week in a fasting state: nothing given, as control (C); oral load of FC (480 mg iron), and 5 minutes of i.v. FO (40 mg iron). Iron dynamics in the body and biological impact on redox-inflammation status during the study (6 hours) were examined.

Results: Significant increases in serum iron and transferrin saturation were seen with both FC and FO. Regarding total iron-binding capacity as the sum of serum iron and unsaturated iron-binding capacity, no changes were found in FC, whereas significant increases were seen in FO (appearance of non-transferrin-binding iron [NTBI]), despite the lower serum iron levels in FO. Compared with C, increases were seen in serum myeloperoxidase (oxidative marker) with accompanying significant decreases in thioredoxin (antioxidant) in FO, whereas no changes were found in FC.

Conclusion: Oral FC differs from i.v. FO in areas such as less NTBI generation and less induction of oxidative stress. The result indicates potential clinical benefits of oral FC in terms of iron supplementation for renal anemia in HD patients.
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http://dx.doi.org/10.1016/j.ekir.2017.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932126PMC
March 2018

Association of geriatric nutritional risk index with infection-related mortality in patients undergoing hemodialysis: The Q-Cohort Study.

Clin Nutr 2019 02 15;38(1):279-287. Epub 2018 Feb 15.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Integrated Therapy for Chronic Kidney Disease, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address:

Background & Aims: The geriatric nutritional risk index (GNRI) is a simple but useful nutritional marker for all-cause mortality and cardiovascular mortality in patients undergoing hemodialysis (HD). However, whether the GNRI can predict infection-related mortality in patients undergoing HD remains unclear, and there is insufficient evidence regarding whether the GNRI improves the predictive value for risk assessment beyond the existing conventional nutritional markers. Here, we investigated the association between the GNRI and infection-related mortality in patients undergoing HD and evaluated the predictive value of GNRI.

Methods: A prospective cohort study was performed on a total of 3436 Japanese HD patients aged ≥18 years. Patients were divided into four groups by quartiles of GNRI: (Quartile 1 [Q1], >100.2; Q2, 95.9-100.2; Q3, 90.8-95.8; Q4, <90.8). We estimated the relationship between GNRI and all-cause mortality and infection-related mortality using a Cox proportional hazards model. To assess the additional predictive value of the GNRI in risk assessment, we compared the c-statistic, net reclassification improvement, and integrated discrimination improvement among serum albumin, serum creatinine, and the GNRI.

Results: During follow-up period (median, 4.0 years), a total of 564 patients died; 120 of these patients died of infectious disease. All-cause mortality and infection-related mortality increased linearly with lower GNRI levels. After adjusting for confounding risk factors, the GNRI was an independent predictor of infection-related mortality as well as all-cause mortality (hazard ratio [HR], 5.89; 95% confidence interval [CI], 2.85-13.8; P < 0.001 for Q4 vs. Q1, HR, 2.62; 95% CI, 1.23-6.24; P = 0.01 for Q3 vs. Q1). Additionally, when the GNRI was incorporated into a model with potential risk factors instead of serum albumin, the c-statistic increased significantly (0.811 vs. 0.821, P = 0.03), and the net reclassification improvement and integrated discrimination improvement was 0.26 (P = 0.005) and 0.005 (P = 0.01). This association was more apparent in the older patients (0.739 vs. 0.760, P = 0.02) than in the younger patients (0.916 vs. 0.912, P = 0.35). Similar results were observed between serum creatinine and the GNRI, but the difference did not reach statistical significance.

Conclusions: Lower GNRI levels are an independent risk factor for infection-related mortality in patients undergoing HD. Moreover, addition of the GNRI to models with standard risk factors significantly improves the predictive ability of infection-related mortality, especially in older patients.
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http://dx.doi.org/10.1016/j.clnu.2018.01.019DOI Listing
February 2019

Hemoglobin concentration and the risk of hemorrhagic and ischemic stroke in patients undergoing hemodialysis: the Q-cohort study.

Nephrol Dial Transplant 2018 05;33(5):856-864

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: The contribution of the hemoglobin concentration to the incidence of hemorrhagic or ischemic stroke in patients undergoing hemodialysis is unclear.

Methods: In total, 3436 patients undergoing prevalent hemodialysis were followed up for 4 years. The primary outcome was the first development of hemorrhagic or ischemic stroke. The baseline hemoglobin concentration was divided into quartiles [hemoglobin (g/dL): Q1, ≤9.7; Q2, 9.8-10.5; Q3, 10.6-11.1; Q4, ≥11.2]. The association between the hemoglobin concentration and each type of stroke was examined using the Kaplan-Meier method and a Cox proportional hazards model.

Results: During the follow-up period, 76 (2.2%) patients developed hemorrhagic stroke and 139 (4.0%) developed ischemic stroke. The 4-year incidence rate of hemorrhagic stroke was significantly higher in patients with lower hemoglobin concentrations. Compared with the quartile of patients with the highest hemoglobin concentrations (Q4), the multivariable-adjusted hazard ratios for hemorrhagic stroke were 1.18 (95% confidence interval, 0.56-2.51), 1.59 (0.82-3.21) and 2.31 (1.16-4.73) in patients in Q3, Q2 and Q1, respectively. No association was identified between the 4-year incidence rate of ischemic stroke and the hemoglobin concentration. Compared with the quartile of patients with the lowest hemoglobin concentrations (Q1), the multivariable-adjusted hazard ratios for ischemic stroke were 1.17 (95% confidence interval, 0.73-1.89), 0.88 (0.51-1.51) and 1.10 (0.66-1.83) in patients in Q2, Q3 and Q4, respectively.

Conclusions: Our results suggest that low hemoglobin concentrations are associated with a high risk of hemorrhagic stroke, but not of ischemic stroke, in patients undergoing hemodialysis.
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http://dx.doi.org/10.1093/ndt/gfx305DOI Listing
May 2018

Ferritin Elevation and Improved Responsiveness to Erythropoiesis-Stimulating Agents in Patients on Ferric Citrate Hydrate.

Kidney Int Rep 2017 May 5;2(3):359-365. Epub 2017 Jan 5.

Fukuoka Renal Clinic, Fukuoka, Japan.

Introduction: In hemodialysis patients on ferric citrate hydrate, the increase in ferritin level is mainly due to the administration of the compound. We investigated possible other factors associated with ferritin level and how erythropoietin resistance index and erythropoiesis in those patients were affected. We looked at ferritin-elevating factors using data from a Japanese phase III long-term clinical trial of ferric citrate hydrate.

Methods: The factors with a strong association with ferritin levels at week 28 were selected by the process of variable selection. In addition, selected factors were analyzed by Mixed Model for Repeated Measurement. Subjects were divided into 3 groups by quantiles (
Results: Dose of ferric citrate hydrate showed the strongest correlation with change of ferritin and the second strongest was the reduction of erythropoiesis-stimulating agents. The mean erythropoietin resistance index was lowered in group 
Discussion: It is suggested that not only iron load but also the erythropoiesis-stimulating agent dose reduction may be involved in ferritin elevation during ferric citrate hydrate treatment, resulting in a decrease of erythropoietin resistance index.
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http://dx.doi.org/10.1016/j.ekir.2016.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678664PMC
May 2017

Secular trends in the incidence of end-stage renal disease and its risk factors in Japanese patients with immunoglobulin A nephropathy.

Nephrol Dial Transplant 2018 06;33(6):963-971

Department of Internal Medicine, Fukuoka Dental College, Fukuoka, Japan.

Background: There are limited data on secular trends in the incidence of end-stage renal disease (ESRD) and frequencies of its risk factors or treatment modalities in patients with immunoglobulin A nephropathy (IgAN).

Methods: This study divided 1255 patients with IgAN into three groups according to the timing of renal biopsy: 1979-89 (n = 232), 1990-99 (n = 574) and 2000-10 (n = 449). The age-adjusted incidence rates, incidence rate ratios and 95% confidence intervals (CIs) for ESRD were calculated by the person-year method and compared using Poisson regression analysis.

Results: A total of 63 patients (5.0%) developed ESRD. The age-adjusted incidence of ESRD decreased significantly over time, i.e. 11.5 per 1000 person-years (95% CI 5.4-24.6) in 1979-89, 6.5 per 1000 person-years (95% CI 1.0-25.2) in 1990-99 and 4.2 per 1000 person-years (95% CI 1.0-17.7) in 2000-10. The proportions of patients with preserved renal function and acute-stage inflammatory histologic changes (i.e. endocapillary hypercellularity and extracapillary proliferation) at the timing of biopsy increased over time, as did the rates of prescriptions of renin-angiotensin system blockers and corticosteroids (all P for trend <0.05). The effect of acute inflammatory histologic lesions on renal prognosis was drastically reduced over time.

Conclusions: These findings suggest that early diagnosis in the acute inflammatory phase and subsequent aggressive treatment may have contributed to the significant downward trend in the incidence of ESRD in patients with IgAN over three decades.
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http://dx.doi.org/10.1093/ndt/gfx223DOI Listing
June 2018

Rationale and design of oBservational clinical Research In chronic kidney disease patients with renal anemia: renal proGnosis in patients with Hyporesponsive anemia To Erythropoiesis-stimulating agents, darbepoetiN alfa (BRIGHTEN Trial).

Clin Exp Nephrol 2018 Feb 28;22(1):78-84. Epub 2017 Jun 28.

Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan.

Background: Renal anemia is an important complication in non-dialysis chronic kidney disease (CKD) patients as well as in dialysis patients. Although recombinant human erythropoietin has dramatically improved prognosis and quality of life in these patients, there have been issues among non-dialysis CKD patients who exhibit hyporesponsiveness to erythropoiesis-stimulating agent (ESA). The causes and definition of ESA hyporesponsiveness, as well as the incidence of renal and cardiovascular disease (CVD) events in such patients, are yet to be clarified.

Methods: This ongoing trial is a multicenter, prospective, observational study of non-dialysis CKD patients with renal anemia. The primary objective is to survey the current realities of the therapy with ESA in Japan and evaluate the correlation between hyporesponsiveness to darbepoetin alfa and CKD progression. The secondary objective is to investigate relationship between ESA hyporesponsiveness and CVD events based on the clinical situation in Japan, and to explore an ESA response index.

Results: The subjects consist of CKD patients with estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m who present renal anemia. The target number of registered cases is 2000 patients, based on estimates of incidences of renal and CVD events from past studies. Renal function and CVD events will be observed for 96 weeks after the initiation of darbepoetin alfa administration. Definitions of ESA hyporesponsiveness will also be investigated.

Conclusion: By clarifying markers and factors involved in ESA hyporesponsiveness and their relationships with renal and CVD events, this ongoing study aims to improve evidence-based therapies for renal anemia in non-dialysis CKD patients.
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http://dx.doi.org/10.1007/s10157-017-1427-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805810PMC
February 2018
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