Peripheral dopamine suppression and elevated cystatin C in early diabetic nephropathy in spontaneously diabetic rats.

Intrarenal dopamine plays a protective role against the development of diabetic nephropathy during the early stages of the disease. In streptozotocin-induced diabetic mice with renal-specific catechol-O-methyl transferase knockout, intrarenal dopamine was found to suppress glomerular hyperfiltration, reduce oxidative stress and inflammation, and inhibit fibrosis. However, although dopamine activation in streptozotocin-induced diabetic models has been shown to provide renal protection, the role of dopamine in models of naturally induced diabetes mellitus is still unclear. In the present study, we orally administered 10 mg/kg benserazide, a peripheral decarboxylase inhibitor, to spontaneously diabetic Torii rats daily to investigate the activation of the renal dopaminergic system during the progression of diabetic nephropathy. Our findings show that peripheral dopamine decreased urinary 8-iso-prostaglandin F2α and suppressed increases in plasma cystatin C levels. This study demonstrates that a reduction in peripheral dopamine can exacerbate renal dysfunction, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration, thereby clarifying the pivotal role of endogenous peripheral dopamine in modulating oxidative stress and kidney performance.NEW & NOTEWORTHY By administering a peripheral decarboxylase inhibitor, we revealed that peripheral dopamine inhibits both the increase in urinary 8-iso-prostaglandin F2α, an oxidative stress marker, and the increase in plasma cystatin C, an early renal dysfunction marker, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration. By visualizing renal dopamine precursor distribution, we highlighted the role of endogenous renal dopamine in oxidative stress and renal function following the onset of glomerular hyperfiltration.

Effectiveness of calcimimetics on fractures in dialysis patients with secondary hyperparathyroidism: meta-analysis of randomized trials.

INTRODUCTION: This study aimed to assess the effectiveness of calcimimetics in reducing the risk of fractures in dialysis patients with secondary hyperparathyroidism (SHPT). MATERIAL AND METHODS: A comprehensive literature search was conducted using PubMed, Embase, and Cochrane Library for articles published through December 9, 2023. The quality of each trial was evaluated using the Cochrane Collaboration tool. Meta-analysis was performed using a random-effects model, and effect measures across studies were synthesized. The risk ratio (RR) and 95% confidence interval (CI) were used to quantify the risk of fracture. RESULTS: We identified seven studies involving 6481 dialysis patients with SHPT. The administration of calcimimetics reduced fracture incidence compared to placebo or conventional treatment (RR: 0.50, 95% CI 0.29-0.88, p = 0.02). Calcimimetics demonstrated a low number needed to treat (NNT) to prevent an incident fracture (NNT: 47). CONCLUSION: The use of calcimimetics offers a significant benefit in reducing the risk of fractures in patients undergoing dialysis with SHPT.

Long-term effectiveness of a primary care practice facilitation program for chronic kidney disease management: an extended follow-up of a cluster-randomized FROM-J study.

BACKGROUND: Practice facilitation program by multidisciplinary care for primary care physicians (PCPs) is expected to improve chronic kidney disease (CKD) outcomes, but there is no clear evidence of its long-term effectiveness. We have previously performed a cluster-randomized controlled trial for 3.5 years (the Frontier of Renal Outcome Modifications in Japan (FROM-J) study) with two arms-group A without the program and group B with the program. We aimed to assess the long-term effectiveness of the practice facilitation program on CKD outcomes via an extended 10-year follow-up of the FROM-J study. METHODS: We enrolled patients who were in the FROM-J study. The primary composite endpoint comprised cardiovascular disease (CVD), renal replacement therapy initiation and a 50% decrease in the estimated glomerular filtration rate (eGFR). The secondary endpoints were survival rate, eGFR decline rate and collaboration rate between PCPs and nephrologists. RESULTS: The occurrence of the primary composite endpoint tended to be lower in group B (group A: 27.1% versus group B: 22.1%, P = 0.051). Furthermore, CVD incidence was remarkably lower in group B (group A: 10.5% versus group B: 6.4%, P = 0.001). Although both mortality and the rate of eGFR decline were identical between both groups, the eGFR decline rate was significantly better in group B than in group A only in patients with stage G3a at enrollment (group A: 2.35 ± 3.87 mL/min/1.73 m2/year versus group B: 1.68 ± 2.98 mL/min/1.73 m2/year, P = 0.02). The collaboration rate was higher in group B. CONCLUSIONS: The CKD practice facilitation program for PCPs reliably decreases CVD events and may reduce the progression of cases to end-stage kidney disease.

Association of polypharmacy with incidence of CKD: a retrospective cohort study.

BACKGROUND: Polypharmacy is common in patients with chronic kidney disease (CKD) and is associated with a decline in kidney function. However, its impact on patients without CKD has not been adequately elucidated. Therefore, we aimed to investigate the association between polypharmacy and the incidence of CKD. METHODS: We conducted retrospective cohort study using 1221 participants who were enrolled in the Fukushima Cohort Study with one or more risk factors of CKD, an estimated glomerular filtration rate (eGFR) of ≥ 60 mL/min/1.73 m2, and without proteinuria. Participants were categorized into three groups based on the number of medications: non-polypharmacy, 0-4 medications; polypharmacy, 5-9 medications; and hyper-polypharmacy, ≥ 10 medications. RESULTS: The median age was 62 years, 49% were men, the median eGFR was 75.4 ml/min/1.73 m2, and the median number of medications was 5. Polypharmacy and hyper-polypharmacy were noted in 506 (41%) and 250 (20%) participants, respectively. During follow-up, 288 participants developed CKD and 67 cardiovascular events were observed. Compared to the non-polypharmacy group, the hyper-polypharmacy group had a higher risk of CKD and cardiovascular events. The adjusted hazard ratios were 1.41 (95% CI1.01-1.99) and 2.24 (95% CI1.05-4.78) for the incidence of CKD and cardiovascular events, respectively. Sensitivity analyses yielded similar findings for the restricted cubic spline function models. CONCLUSIONS: Hyper-polypharmacy is associated with a higher risk of CKD and cardiovascular events.

Blood data trends of children in Fukushima after the Great East Japan Earthquake: Fukushima health management survey.

BACKGROUND: After the Great East Japan Earthquake on March 11, 2011 and the subsequent accident at the Tokyo Electric Power Company-operated Daiichi Nuclear Power Plant, the Fukushima Prefecture government initiated the Fukushima Health Management Survey (FHMS) to assess the long-term health effects of the disaster on Fukushima residents. The blood tests of children aged ≤15 years between 2011 and 2012 did not reveal any changes regarding peripheral blood data; however, long-term monitoring is still necessary. Therefore, this study aimed to investigate the long-term health status of children aged ≤15 years who had evacuated the Fukushima Prefecture. METHODS: From 2011 to 2018, 71,250 evacuees aged 15 years or younger participated in the FMHS and were subjected to blood tests. By analyzing the data of the comprehensive health check survey managed by the FHMS, we examined the changes in hemoglobin (Hb) levels, white blood cell (WBC) counts, including fractions, and platelet (PLT) counts among children from 2011 to 2018. RESULTS: Minor fluctuations in Hb levels, PLT counts, and WBC counts were observed during the study period, but the central 95% intervals of distribution of the laboratory values were generally within previously reported reference intervals. In particular, there was no increase in the proportions of patients with anemia, polycythemia, or deviating WBC counts. CONCLUSION: From 2011 to 2018, there was no increase in the percentages of children with anemia, polycythemia, or deviating WBC counts among the Fukushima Prefecture evacuees.

Changes in Metabolomic Profiles Induced by Switching from an Erythropoiesis-Stimulating Agent to a Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor in Hemodialysis Patients: A Pilot Study.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs.

Risks of femoral localized periosteal thickening in patients with autoimmune inflammatory rheumatic diseases.

OBJECTIVES: The incidence of femoral localized periosteal thickening (LPT), which can precede atypical femoral fracture (AFF), is not low (1-10%) in Japanese patients with autoimmune inflammatory rheumatic diseases (AIRDs). We explored the associations between underlying AIRDs and the prevalence of LPT. METHODS: We conducted post hoc analyses of two cohorts that included a total of 280 Japanese women, 105 of whom had AIRDs and had been taking bisphosphonate (BP) and prednisolone (PSL) and 175 of whom had rheumatoid arthritis (RA). RESULTS: LPT was detected in a total of 18 patients (6.4%) and 3 (1.1%) developed AFFs. RA was negatively correlated with LPT. A disease other than RA requiring glucocorticoid treatment, BP use ≥5 years, PSL use ≥7 years, and a PSL dose ≥5.5 mg/day were positively correlated with LPT. After adjusting for age, diabetes mellitus, and BP duration or daily PSL dose, RA was no longer associated with LPT. CONCLUSIONS: LPT in Japanese patients with AIRDs was associated with BP and glucocorticoid treatment rather than underlying AIRDs. When PSL dose ≥5.5 mg/day is required long-term [typically combined with long-term BP treatment (≥5 years)], clinicians need to pay particular attention in cases LPT and AFF as well as glucocorticoid-induced osteoporosis.

Smoking and risk of fractures requiring hospitalization in haemodialysis patients: a nationwide cohort study in Japan.

BACKGROUND: Smoking is a well-established lifestyle risk factor for fractures in the general population, but evidence specific to haemodialysis populations is lacking. This nationwide cohort study used data from the Japanese Society for Dialysis Therapy Renal Data Registry to examine the association between smoking status and fractures. METHODS: A total of 154 077 patients (64.2% men; mean age 68 years) aged ≥20 years undergoing maintenance haemodialysis thrice weekly at the end of 2016 were followed for 1 year. Among these, 19 004 (12.3%) patients were current smokers. Standardized incidence rate ratios of hospitalization due to any fracture were calculated and analysed by multivariable logistic regression analysis, controlling for potential confounders. Propensity score (PS) matching and subgroup analyses were also performed as sensitivity analyses. RESULTS: During the 1-year follow-up period, 3337 fractures requiring hospitalization (1201 hip, 479 vertebral and 1657 other fractures) occurred in 3291 patients. The age- and sex-standardized incidence ratio for current smokers was 1.24 (95% confidence interval 1.12-1.39) relative to non-smokers. Standardized incidence ratios were similar after stratification by age group and sex. Multivariable logistic regression analysis revealed a 1.25-fold higher risk of any fracture requiring hospitalization (95% confidence interval 1.10-1.42) in current smokers relative to non-smokers in a fully adjusted model. PS matching showed similar results (odds ratio 1.25; 95% confidence interval 1.05-1.48). Subgroup analyses for baseline covariates revealed no significant interactions. CONCLUSIONS: Smoking is a significant risk factor for any fracture requiring hospitalization in haemodialysis patients.

Relationship Between Risk of Hyper-Low-density Lipoprotein Cholesterolemia and Evacuation After the Great East Japan Earthquake.

BACKGROUND: The Great East Japan Earthquake and the Fukushima Daiichi nuclear disaster forced the evacuation of residents and led to many changes in lifestyle for the evacuees. The Comprehensive Health Check was implemented to support the prevention of lifestyle-related disease and we analyzed the effect of prolonged evacuation (average of 3.0 years) on the new onset of hyper-LDL cholesterolemia. METHODS: The study participants were Japanese adults living near the Fukushima Daiichi nuclear power plant in Fukushima Prefecture. Annual health checkups focusing on metabolic syndromes were conducted for persons ≥40 years by the Specific Health Checkup. Based on data from annual checkups from 2011 or 2012, we followed 18,670 participants without hyper-LDL cholesterolemia who underwent at least one other annual checkup during 2013-2015. RESULTS: We found that the new onset of hyper-LDL cholesterolemia was 31% higher in evacuees than in non-evacuees. Evacuees had a significantly higher prevalence of obesity, hypertension, and diabetes, and higher frequency of weight change. Furthermore, logistic regression model analysis showed that the evacuation was significantly associated with the new onset of hyper-LDL cholesterolemia after adjusting age, gender, body mass index, smoking habit, alcohol consumption, diabetes, weight change, sleep deprivation, and exercise. CONCLUSION: The findings of the present study suggest that prolonged evacuation after a disaster is a risk factor for the new onset of hyper-LDL cholesterolemia, and lead to an increase in cardiovascular disease. It is therefore important to follow-up evacuees and recommend lifestyle changes where necessary.

Lower trabecular bone score is associated with an increased incidence of localized femoral periosteal thickening.

INTRODUCTION: Femoral localized periosteal thickening (LPT, also termed "beaking") of the lateral cortex often precedes an atypical femoral fracture (AFF). Bisphosphonate (BP) use, glucocorticoid use, and Asian race are major risk factors for developing such fractures. The aim of this study was to determine whether the trabecular bone score (TBS) reflecting the lumbar trabecular microarchitecture was related to LPT in glucocorticoid-treated Japanese patients with autoimmune diseases. MATERIALS AND METHODS: We retrospectively investigated 111 women with autoimmune diseases treated with prednisolone (PSL) who had undergone both femoral X-ray and dual-energy X-ray absorptiometry of the L1 - L4 lumbar vertebrae and for whom TBS could be evaluated for two or more of these. RESULTS: Femoral LPT was evident in the X-rays of 18 of 111 patients (16.2%). Higher body mass index (BMI), longer duration of PSL use and longer duration of BP use were significant in patients with LPT compared to those without. The TBS was significantly lower in patients with LPT than in those without (1.314 ± 0.092 vs. 1.365 ± 0.100, p = 0.044); however, the lumbar bone mineral density did not differ significantly (0.892 ± 0.141 vs. 0.897 ± 0.154 g/cm2, p = 0.897). TBS was significantly associated with LPT (odds ratio, 0.004; 95% CI, 0 - 0.96; p = 0.048), but not in the multivariate analysis including BMI, duration of PSL use and duration of BP use. CONCLUSIONS: The TBS was lower in glucocorticoid-treated Japanese women with autoimmune diseases with LPT than in those without LPT, and deteriorated trabecular microarchitecture influenced by longer use of BP and glucocorticoid might be associated with the development of LPT.

Long-term excess mortality after hip fracture in hemodialysis patients: a nationwide cohort study in Japan.

INTRODUCTION: Fracture dialysis patients have a higher risk of 1-year mortality compared with non-fracture dialysis patients. However, it is unclear whether excess mortality persists for more than a year. MATERIALS AND METHODS: We conducted a nationwide cohort study in 162,360 hemodialysis patients in Japan. Study outcomes were 5-year all-cause mortality and cause-specific mortality. Cox proportional hazards regression was used to examine the association between hip fracture and mortality in two cohorts: the full cohort, which included potential confounders as covariates in multivariable-adjusted regression models, and the propensity score-matched cohort. RESULTS: Crude mortality rates for fracture patients were double those of non-fracture patients and persisted during the 5-year period. The association between hip fracture and mortality was significant even after adjusting for premorbid conditions (hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.13-1.32). Similar findings were observed in the propensity score-matched cohort of 2410 patients (HR 1.20, 95% CI 1.05-1.36). While cause-specific mortality rates for all categories, with the exception of sudden deaths, were higher for fracture patients relative to non-fracture patients in the full unmatched cohort, only the mortality rate for heart disease was significantly higher for fracture patients relative to non-fracture patients in the propensity score-matched cohort. CONCLUSION: Excess mortality persisted for many years after hip fracture in hemodialysis patients, and was still present after adjusting for several premorbid conditions and propensity score matching.

Effect of sucroferric oxyhydroxide on gastrointestinal microbiome and uremic toxins in patients with chronic kidney disease undergoing hemodialysis.

BACKGROUND: In patients with chronic kidney disease (CKD), dysbiosis in the gastrointestinal microbiome is thought to be associated with increased production of uremic toxins, such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS). Sucroferric oxyhydroxide (SFO), an iron-based phosphate binder, may affect the gastrointestinal microbiome and the production of uremic toxins. We aimed to examine whether SFO administration affected distribution of gastrointestinal microbiome and serum uremic toxin levels in CKD patients undergoing hemodialysis. METHODS: In this single-center, open-label, interventional study, 18 maintenance hemodialysis patients with hyperphosphatemia were prescribed with SFO. We collected serum samples before and after 3 months of administration, and serum levels of IS and PCS were measured. A control group of 20 hemodialysis patients without SFO was evaluated. We evaluated gastrointestinal microbiome of patients pre- and post-SFO administration by 16S rDNA sequencing and bioinformatics analysis. RESULTS: Serum IS and PCS levels were significantly elevated after administration of SFO (IS before 2.52 ± 1.60 mg/dl vs. after 3.13 ± 1.51 mg/dl, P = 0.008; PCS before 2.32 ± 2.44 mg/dl vs. after 3.45 ± 2.11 mg/dl, P = 0.002), while serum IS and PCS levels did not change in the control group. Microbiome analysis in the SFO group showed no significant change in diversity and major components in phylum, class, order, family, gene, and species. CONCLUSION: Administration of SFO increased the serum levels of IS and PCS with no change of major components of gastrointestinal microbiome.

Blood pressure control in chronic kidney disease according to underlying renal disease: the Fukushima CKD cohort.

BACKGROUND: Inadequate blood pressure control is one of the important causes of chronic kidney disease (CKD), but only a limited number of reports have examined blood pressure control in Japanese patients with pre-dialysis CKD. Differences in blood pressure control due to underlying renal disease in pre-dialysis patients with CKD were investigated in the present study using the baseline data of the Fukushima CKD cohort study. METHODS: The study involved 1351 CKD patients, classified by underlying disease of primary renal disease, hypertensive nephropathy, diabetic nephropathy, other nephropathies, or unknown. Target blood pressure of CKD patients was defined as < 130/80 mmHg in patients under 75 years old with diabetes and/or proteinuria, and < 140/90 mmHg in other patients. RESULTS: The achievement rate of target systolic blood pressure was lower in the diabetic and hypertensive nephropathy groups than in the primary renal disease group (33.3%, 46.0% vs. 68.1%, p < 0.001). However, the number of antihypertensive medications increased in the diabetic and hypertensive nephropathy groups compared to the primary renal disease group (2.16, 2.04 vs. 1.55, p < 0.001). Inadequate blood pressure control was independently related to the underlying renal disease, with a significant difference between diabetic nephropathy and primary renal disease (odds ratio 3.19; 95% confidence interval, 2.16-4.69; p < 0.001). CONCLUSION: This study showed that blood pressure control differs by the underlying renal disease. Blood pressure control was poor especially in diabetic nephropathy despite multidrug combination antihypertensive treatment. It is necessary to verify whether strict blood pressure control improves patients' prognosis in diabetic nephropathy.

Better remission rates in elderly Japanese patients with primary membranous nephropathy in nationwide real-world practice: The Japan Nephrotic Syndrome Cohort Study (JNSCS).

BACKGROUND: The aim of the present study was to clarify the prevalence of immunosuppressive drug use and outcomes in elderly and non-elderly patients with primary membranous nephropathy (MN) in nationwide real-world practice in Japan. PATIENTS AND METHODS: Between 2009 and 2010, 374 patients with primary nephrotic syndrome were enrolled in the cohort study (The Japan Nephrotic Syndrome Cohort Study, JNSCS), including 126 adult patients with MN. Their clinical characteristics were compared with those of nephrotic patients with primary MN registered in a large nationwide registry (The Japan Renal Biopsy Registry, J-RBR). Outcomes and predictors in the elderly (≥ 65 years) and non-elderly groups were identified. RESULTS: Similar clinical characteristics were observed in JNSCS patients and J-RBR patients (n = 1808). At the early stage of 1 month, 84.1% of patients were treated with immunosuppressive therapies. No significant differences were observed in therapies between age groups. However, elderly patients achieved complete remission (CR) more frequently than non-elderly patients, particularly those treated with therapies that included corticosteroids. No significant differences were noted in serum creatinine (sCr) elevations at 50 or 100%, end-stage kidney disease, or all-cause mortality between age groups. Corticosteroids were identified as an independent predictor of CR (HR 2.749, 95%CI 1.593-4.745, p = 0.000) in the multivariate Cox's model. sCr levels, hemoglobin levels, immunosuppressants, clinical remission, and relapse after CR were independent predictors of sCr × 1.5 or × 2.0. CONCLUSION: Early immunosuppressive therapy including corticosteroids for primary MN showed better remission rates in elderly patients in a nationwide cohort study.

Functional impairment attenuates the association between high serum phosphate and mortality in dialysis patients: a nationwide cohort study.

BACKGROUND: Both functional impairment and abnormalities in mineral and bone disorder (MBD) parameters are well-known predictors of mortality in dialysis patients. However, previous studies have not evaluated whether functional impairment modifies the association between MBD parameters and mortality. METHODS: A nationwide prospective cohort study was conducted using data from the Japanese Society for Dialysis Therapy Renal Data Registry collected at the end of 2009 and 2010. The Eastern Cooperative Oncology Group performance status (PS) was used to assess functional status. Cox proportional hazards models were used to assess the associations of baseline functional status, serum phosphate, albumin-corrected calcium and intact parathyroid hormone (PTH) with 1-year all-cause mortality. RESULTS: By 31 December 2010, 18 447 of 220 054 prevalent dialysis patients (8.4%) had died. Mortality significantly increased with worsening PS grade. PS grade modified the association of serum phosphate levels with mortality (Pinteraction = 0.001). Worsening PS grade attenuated the association of hyperphosphatemia (≥7.4 mg/dL) with mortality, and hyperphosphatemia was no longer significant on mortality among patients with the worst PS grade (hazard ratio = 1.1, 95% confidence interval 0.88-1.39), compared with the level between 3.5 and 4.7 mg/dL. In contrast, hypophosphatemia (<3.5 mg/dL) had a greater adjusted risk of mortality irrespective of PS grade. Serum-corrected calcium (Pinteraction = 0.26) and intact PTH (Pinteraction = 0.17) showed consistent associations with mortality irrespective of PS grade. Findings were robust in several sensitivity analyses. CONCLUSIONS: Functional impairment was significantly associated with 1-year mortality and attenuated the effect of hyperphosphatemia on mortality among prevalent dialysis patients.

Hip Fracture Trends in Japanese Dialysis Patients, 2008-2013.

BACKGROUND: Contrary to observations of decreasing rates in Western nations for the past 2 decades, age-adjusted rates of hip fracture in the general population in Japan have continually increased. This study aimed to analyze recent changes in trends of hip fracture incidence among Japanese dialysis patients between 2008 and 2013. STUDY DESIGN, SETTING, & PARTICIPANTS: Using data from the Japanese Society for Dialysis Therapy Renal Data Registry database from 2007 to 2013, we created a point-prevalent study cohort for each study year. Prevalent dialysis cohorts included patients 20 years or older without a history of hip fracture who were receiving maintenance dialysis in Japan on December 31 of each year. FACTORS: Age, sex, and calendar year. OUTCOMES: Hip fracture incidence rates. MEASUREMENTS: Unadjusted hip fracture rates were estimated using number of events per 1,000 patient-years in each year and then standardized for age to the 2013 dialysis population. Average annual percentage of change in rates and corresponding 95% CI were computed for trend by joinpoint regression analysis. RESULTS: During the study period, 6,615 and 4,963 hip fractures were recorded among female and male dialysis patients, respectively. Age-standardized hip fracture rates decreased steadily from 2008 (21.1/1,000 patient-years) to 2013 (17.7/1,000 patient-years) among women, but remained constant from 2008 (8.6/1,000 patient-years) through 2013 (8.2/1,000 patient-years) among men. Decreases in the joinpoint trend for hip fracture were significant among female (-3.6% [95% CI, -6.9 to -0.2] per year), but not among male, dialysis patients (-1.4% [95% CI, -5.7 to 3.0] per year) from 2008 through 2013. LIMITATIONS: Only the first hip fracture event was considered in calculations of fracture rates. CONCLUSIONS: In contrast to the increasing incidence of hip fracture in the general Japanese population, we found that the incidence of hip fracture in Japanese dialysis patients between 2008 and 2013 decreased among women, but did not change in men.

Premature mortality due to nephrotic syndrome and the trend in nephrotic syndrome mortality in Japan, 1995-2014.

BACKGROUND: This study analysed the trend in mortality from nephrotic syndrome in Japan from 1995 to 2013. Moreover, to better understand premature death from nephrotic syndrome, the average years of life lost due to nephrotic syndrome were estimated. METHODS: National death certificate data were evaluated. Age-standardised mortality rates from nephrotic syndrome were calculated by direct standardisation using the World Standard Population. Trends for average annual changes in percentages were determined by joinpoint regression analysis. Average years of life lost were estimated by dividing total years of life lost by the number of deaths from nephrotic syndrome. Years of life lost were estimated by the constant end-point method, with 65 years as the endpoint. Average years of life lost due to malignant neoplasms, the leading cause of death in Japan, were estimated for comparison. RESULTS: There were 9945 deaths (4872 men and 5073 women) during the study period. The numbers of deaths and crude overall mortality rates increased, while age-standardised mortality rates continuously decreased, for both sexes. The annual percentage changes were -1.9% [95% confidence interval (CI), -2.3 to -1.4%] for men and -3.5% (95% CI -4.1 to -2.9%) for women. The average years of life lost due to nephrotic syndrome decreased during the study period, but were greater than for patients who died of malignant neoplasm. CONCLUSIONS: Mortality and premature mortality rates from nephrotic syndrome significantly decreased in Japan between 1995 and 2014. Despite these improvements, nephrotic syndrome patients ≤65 years of age still have a poor prognosis.

Effect of ferric citrate hydrate on FGF23 and PTH levels in patients with non-dialysis-dependent chronic kidney disease with normophosphatemia and iron deficiency.

BACKGROUND: In patients with normophosphatemia with chronic kidney disease (CKD), fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) increase urinary phosphate excretion while maintaining serum phosphate within the normal range. Recent reports have shown that, in this stage, phosphate binders do not decrease serum FGF23 and PTH levels. Iron deficiency promotes transcription of FGF23 and iron-supplementation for iron deficiency decreases serum FGF23 levels. We hypothesized that ferric citrate hydrate, an iron-based phosphate binder, will decrease serum FGF23 levels in patients with non-dialysis-dependent CKD with normophosphatemia and iron deficiency. METHODS: This was a single-center, randomized, open-label interventional study. The inclusion criteria were as follows: (1) eGFR < 45 mL/min/1.73 m2, (2) normophosphatemia, (3) iron deficiency. Patients were assigned to the following groups: ferric citrate hydrate (FCH)-group, sodium ferrous citrate (SFC)-group, and control-group. After 12 weeks of intervention, we evaluated serum FGF23 levels and CKD-mineral bone disorder markers. RESULTS: There were 17 patients in the FCH-group, 14 in the SFC-group, and 9 in the control-group. The serum ferritin levels increased in the FCH-group and SFC-group compared with baseline. Serum FGF23 levels were unchanged; the change in the FCH-group was from 52.91 RU/mL (42.48-72.91) to 40.00 RU/mL (30.30-58.13) (P = 0.1764). However, in the FCH-group, serum PTH levels significantly decreased compared with baseline, from 68.00 pg/mL (49.00-141.00) to 60.00 pg/mL (44.00-144.00) (P = 0.0101). CONCLUSION: Iron-based phosphate binder did not decrease serum FGF23 levels, but decreased serum PTH levels.

Regional variations in immunosuppressive therapy in patients with primary nephrotic syndrome: the Japan nephrotic syndrome cohort study.

BACKGROUND: The lack of high-quality clinical evidences hindered broad consensus on optimal therapies for primary nephrotic syndromes. The aim of the present study was to compare prevalence of immunosuppressive drug use in patients with primary nephrotic syndrome across 6 regions in Japan. METHODS: Between 2009 and 2010, 380 patients with primary nephrotic syndrome in 56 hospitals were enrolled in a prospective cohort study [Japan Nephrotic Syndrome Cohort Study (JNSCS)], including 141, 151, and 38 adult patients with minimal change disease (MCD), membranous nephropathy (MN), and focal segmental glomerulosclerosis (FSGS), respectively. Their clinical characteristics were compared with those of patients registered in a large nationwide registry of kidney biopsies [Japan Renal Biopsy Registry (J-RBR)]. The regional prevalence of use of each immunosuppressive drug was assessed among adult MCD, MN, and FSGS patients who underwent immunosuppressive therapy in the JNSCS (n = 139, 127, and 34, respectively). Predictors of its use were identified using multivariable-adjusted logistic regression models. RESULTS: The clinical characteristics of JNSCS patients were comparable to those of J-RBR patients, suggesting that the JNSCS included the representatives in the J-RBR. The secondary major immunosuppressive drugs were intravenous methylprednisolone [n = 33 (24.6%), 24 (19.7%), and 9 (28.1%) in MCD, MN, and FSGS, respectively] and cyclosporine [n = 25 (18.7%), 62 (50.8%), and 16 (50.0%), respectively]. The region was identified as a significant predictor of use of intravenous methylprednisolone in MCD and MN patients. CONCLUSION: Use of intravenous methylprednisolone for MCD and MN differed geographically in Japan. Its efficacy should be further evaluated in a well-designed trial.

Chronic kidney disease and fragility fracture.

Osteoporosis is defined simply as "a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Thus, any bone lesion that causes fragility fracture is osteoporosis, which has quite heterogeneous backgrounds. Chronic kidney disease-related bone and mineral disease (CKD-MBD) is defined as "a systemic disorder of mineral and bone metabolism due to CKD, which is manifested by abnormalities in bone and mineral metabolism and/or extra-skeletal calcification". Although CKD-MBD is one of the possible causes of osteoporosis, we do not have evidences that CKD-MBD is the only or crucial determinant of bone mechanical strength in CKD patients. The risk of hip fracture is considerably high in CKD patients. Drugs that intervene in systemic mineral metabolism, indeed, lead to the improvement on bone histology in CKD patients. However, it remains unclear whether the intervention in systemic mineral metabolism also improves bone strength, today. Thus, the use of drugs that directly act on bone and the introduction of fracture liaison concept are promising strategies for fragility fracture prevention among CKD patients, as well as treatment for CKD-MBD.